10 1080@1744666X 2019 1705785

Expert Review of Clinical Immunology
ISSN: 1744-666X (Print) 1744-8409 (Online) Journal homepage: https://www.tandfonline.com/loi/ierm20
Infection risk in patients undergoing treatment

for inflammatory arthritis: non-biologics versus
biologics
Ying-Ming Chiu & Der-Yuan Chen
To cite this article: Ying-Ming Chiu & Der-Yuan Chen (2019): Infection risk in patients undergoing
treatment for inflammatory arthritis: non-biologics versus biologics, Expert Review of Clinical
Immunology, DOI: 10.1080/1744666X.2019.1705785
To link to this article: https://doi.org/10.1080/1744666X.2019.1705785
Accepted author version posted online: 18

Dec 2019.
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Publisher: Taylor & Francis & Informa UK Limited, trading as Taylor & Francis
Group
Journal: Expert Review of Clinical Immunology
DOI: 10.1080/1744666X.2019.1705785
Infection risk in patients undergoing treatment for inflammatory arthritis:
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non-biologics versus biologics
Ying-Ming Chu1,2, Der-Yuan Chen1,2,3,4,5*
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Rheumatology and Immunology Center, China Medical University Hospital,
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Taichung, Taiwan
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2
College of Medicine, China Medical University, Taichung, Taiwan
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Translational Medicine Laboratory, Rheumatic Diseases Research Center, China
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Medical University Hospital, Taichung, Taiwan

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4
Ph.D. Program in Translational Medicine and Rong Hsing Research Center for
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Translational Medicine, National Chung Hsing University, Taichung, Taiwan
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Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical
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University, Taichung, Taiwan
*Correspondence: Der-Yuan Chen, MD, PhD, Rheumatology and Immunology Center,
China Medical University Hospital, No. 2, Yude Road, Taichung, 40447, Taiwan. Tel:
886-4-22052121, extension 4628; fax: 886-4-22073812; e-mail:
Information Classification: General

2
dychen1957@gmail.com
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List of abbreviations
ABT: abatacept; ADA: adalimumab; AS: ankylosing spondylitis; bDMARDs:
biologic disease modifying anti-rheumatic drugs; CKD: chronic kidney disease;
COPD: chronic obstructive pulmonary disease; CS: corticosteroids; CsA:
cyclosporine A; csDMARDs: conventional synthetic disease modifying
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anti-rheumatic drugs; CZP: certolizumab; DAAs: direct-acting antiviral agents; DM:
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diabetes mellitus; DOT: directly observed therapy; EIN: Emerging Infections
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Network; ETN: etanercept; GOL: golimumab; GPRD: General Practice Research
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Database; HBV: hepatitis B virus; HBVr: HBV reactivation; HBsAg+:
HBsAg-positive; HBsAg-/anti-HBc+: HBsAg-negative anti-HBc antibodies-positive;

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HCV: hepatitis C virus; HCQ: hydroxychloroquine: IFX: infliximab; IL-6:

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interleukin-6; JAK: Janus kinase; LEF: leflunomide; LTBI: latent tuberculosis
infection; mAb: monoclonal antibody; MTX: methotrexate; OR: odds ratio; PA:
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psoriatic arthritis; PMS: post-marketing surveillance; RA: rheumatoid arthritis; TNF:

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tumor necrosis factor; TNFi: tumor necrosis factor inhibitor; SC: secukinumab; SSZ:
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sulfasalazine; TOZ: tocilizumab; RCT: randomized controlled trial; RR: relative risk;
RTX: rituximab; 3HP: 3-month once-weekly isoniazid plus rifapentine; TB:
tuberculosis; tsDMARDs: targeted synthetic disease modifying anti-rheumatic drugs;
UTK: ustekinumab; WHO: World Health Organization

4
Abstract
Introduction: Despite the therapeutic effectiveness of biologics targeting immune
cells or cytokines in patients with inflammatory arthritis, which reflects their
pathogenic roles, an increased infection risk is observed in those undergoing
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biological treatment. However, there are limited data regarding the comparison of
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infection risks in inflammatory arthritis patients treated with non-biologics
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(csDMARDs), biologics (bDMARDs), including tumor necrosis factor (TNF)
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inhibitors and non-TNF inhibitors, or targeted synthetic (ts)DMARDs.
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Areas covered: Through a review of English-language literature as of 30 June 2019,
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we focus on the existing evidence on the risk of infections caused by bacteria,
Mycobacterium tuberculosis, and hepatitis virus in inflammatory arthritis patients

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undergoing treatment with csDMARDs, bDMARDs, or tsDMARDs.

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Expert opinion: While the risks of bacterial and mycobacterial infection are
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increased in arthritis patients treated with csDMARDs, the risks are further higher in
those receiving bDMARDs therapy, particularly TNF inhibitors. Regarding HBV

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infection, antiviral therapy may effectively prevent HBV reactivation in patients
receiving bDMARDs, especially rituximab. However, more data are needed to
establish effective preventive strategies for HBsAg-negative/HBcAb-positive patients.
It seems safe to use cyclosporine and TNF inhibitors in patients with HCV infection,

5
while those undergoing rituximab therapies should be frequently monitored for HCV
activity.
Keywords: Infection risk, treatment, non-biologics, biologics, inflammatory arthritis
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Article highlights:
1. Both csDMARDs and bDMARDs increase the risk of bacterial infection,
especially pneumonia. The risk associated with bDMARDs is higher than with
csDMARDs.
2. There are increased TB risks in adult arthritis patients treated with the inhibitors to
TNF-α or Janus kinases in TB-endemic areas, while it seems safe to use non-TNF
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bDMARDs.
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3. Prophylactic antiviral therapy in HBsAg-positive patients can effectively prevent
HBV reactivation; however, more data are needed for occult HBV infection to set
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a preventive strategy.
4. Although limited data indicate low risk of HCV reactivation in patients treated
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with bDMARDs or tsDMARDs, a collaboration between rheumatologists and
hepatologists is suggested in using DAAs according to the risk stratification.

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5. The implementation of preventive strategies is needed to reduce the infection risks
in inflammatory arthritis patients undergoing therapies with bDMARDs or

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tsDMARDs.
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1. Introduction
Inflammatory arthritis is a chronic inflammatory disease marked by persisted
synovitis and joint erosion [1]. The activated T-cells, B-cells, and pro-inflammatory
cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 can promote
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synovitis, cartilage damage and bone destruction [1-3]. The pathogenic roles of the
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immune cells and pro-inflammatory cytokines in rheumatoid arthritis (RA) are
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evidenced by the therapeutic effectiveness of biologics targeting these immune cells
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or cytokines [2-8]. Therefore, the biologic agents with or without concomitant
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conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) are
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increasingly used to treat RA patients [9,10]. Recently, the inhibitors to a small
molecule Janus kinase (JAK) has been approved for the treatment of adult patients
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with RA [11]. To inhibit peripheral arthritis in ankylosing spondylitis (AS) and

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psoriatic arthritis (PsA), like RA, the therapy varies from the use of csDMARDs to
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biologics such as TNF inhibitors [12-14].
Patients with inflammatory arthritis have higher risks of infectious morbidity and
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mortality [15-18], which may be due to disease-related immune dysfunction [19,20]
or the immunosuppressive effects of therapeutic agents [21,22]. Given that
pro-inflammatory cytokines are essential for human defense, the inhibitors to
cytokines or JAK may increase the risk of infections or reactivation of latent

8
tuberculosis infection (LTBI) or hepatitis virus infection [21-25]. Although
accumulating reports have indicated an increased risk of infections in adult patients
undergoing TNF-α inhibitors therapy for arthritis, the infection risks associated with
non-TNF-α inhibitors and oral JAK inhibitors were rarely addressed [25-26]. Similar
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to adult patients with inflammatory arthritis, infection risks also increased in children
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treated with biologic therapy [27-28].
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Hepatitis B virus (HBV) infection is an important public health issue worldwide and
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nearly 240 million people are chronically infected [29]. A substantial number of
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inflammatory arthritis patients who have coexisting HBV infection develop HBV
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reactivation (HBVr) due to the use of immunosuppressive agents including biologics,
particularly in HBV endemic area [30-31]. In contrast to hepatitis B virus (HBV)

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reactivation, hepatitis C virus (HCV) reactivation is relatively uncommon in patients

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with inflammatory arthritis [32]. In addition, there are scarcely any recommendation
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for HCV screening for arthritis patients starting therapy with csDMARDs, biologics,
or oral JAK inhibitors [33,34].

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Consequently, we aimed to review the impacts of treatment with non-biologics,
biologics (TNF-α inhibitors and non-TNF-α inhibitors), and JAK inhibitors on the
risks of bacterial infections, reactivation of LTBI and viral hepatitis in adult or
children patients with inflammatory arthritis, including RA, AS, and PsA.

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2. Methods
The present review focuses on the existing evidence on the risks of infections caused
by bacteria, Mycobacterium tuberculosis, hepatitis B or C virus in patients receiving
non-biologics (csDMARDs), biologics (bDMARDs), or small molecular inhibitors (so
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called targeted synthetic DMARDs, tsDMARDs) for inflammatory arthritis. We
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searched MEDLINE database using the PubMed interface and reviewed
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English-language literatures as of 30 June 2019, from 1971 to 2019. The investigated
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drugs include commonly used csDMARDs, the available bDMARDs including
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TNF-α inhibitors as well as non-TNF-α inhibitors, biosimilars, and oral tsDMARDs
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(JAK inhibitors as well as phosphodiesterase 4 inhibitor).
3. Data on the risk of bacterial infection associated with csDMARDs, bDMARDs,

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and tsDMARDs therapies for RA, AS and PsA

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RA patients are at higher risk of bacterial infection than general population [35], and
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infection complications are also important causes of mortality and morbidity in RA
patients. The reasons for higher infection rate in RA may be related to disability as
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well as immobility associated with active disease, increased rate of cigarette smoking,
the presence (often subclinical) of inflammatory lung disease, and an
immunosuppression caused by disease itself or the used medications (csDMARDs,
bDMARDs, or tsDMARDs) [36].

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3.1. The csDMARDs
3.1.1. Corticosteroids (CS)
Corticosteroid could impair phagocyte function, suppress cell-mediated immunity and
contribute to susceptibility to infection [37]. A meta-analysis drawing on randomized
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clinical trials (RCT) and observational studies compared the infection risk associated
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with CS use and non-use among RA patients. The result showed an increased relative
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risk (RR) (1.67, 1.47-1.87) with a positive dose-response effect in CS users [38].
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3.1.2. Methotrexate (MTX)
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Although descriptive analysis showed MTX use increased infection risk in RA
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patients [39,40], a combination of csDMARD therapy makes it difficult to estimate
the true risk linked to MTX. In a US registry study enrolling 16788 RA patients, the
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results showed no association of between MTX use and pneumonia after adjusted for
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age, sex, smoking status, comorbidities, disease factor and co-medication [41]. An
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observational study from Canada claims databases reported slightly increased risk of
pneumonia associated with MTX use (RR 1.2; 95% CI 1.0-1.3) [42], while another
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claim database from US revealed decreased infection risk in MTX user [43].
Notwithstanding the inconsistent results above, the slightly increased risk of infection
maybe counterbalanced by effective control of rheumatic disease and improved
function.
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3.1.3. Leflunomide (LEF)
In a cohort study following 171 RA patients using LEF, the incidence of severe
infection was 3.3% person-year [44]. However, most of those patients had
concomitant medication such as corticosteroids or MTX, which also may contribute to
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infection risk. According to an analytics of a large claim database, after controlling
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concomitant medication and other risk factors, LEF was still an independent risk
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factor for bacterial pneumonia [41].
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3.1.4. Hydroxychloroquine (HCQ), sulfasalazine (SSZ), and cyclosporine A (CsA)
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A research on US registry data found that, after adjusted for co-medication and other
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confounders, SSZ was not associated with increased pneumonia risk [41]. But another
study using General Practice Research Database (GPRD) showed slightly increased
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risk of septic arthritis linked to SSZ use [45]. Although CsA is associated with higher
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risk of infection in transplanted patients, it did not significantly influence the

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infectious morbidity in nontransplantation settings [46]. About the infection risk of
related to HCQ, several studies using large database have confirmed its safety [41,43].
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3.2. The bDMARDs
3.2.1. TNF-α inhibitors (TNFi)
The most common bacterial infection linked to anti-TNF is pneumonia, followed by
skin or soft tissue infection; other bacterial infections include bone/joint and urinary
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tract infection (Table 1) [47-52]. Several recent studies show a differential risk of
infection among the first three anti-TNF agents: increase risk with infliximab when
compare with etanercept or adalimumab [53-54]. Besides, the significantly increased
infection risk was noted during the first year only [49]; however, this may be due to
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selection bias [55] (high-risk patients dropped out of the biologic cohort due to side
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effects or deterioration of health condition). Despite the high infection risk associated
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with anti-TNF agents, the risk has gradually decreased in recent years, presumably
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thanks to the updated treatment criteria and guidelines [56].
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3.2.2. B-cell depletion agent, rituximab (RTX)
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According to a meta-analysis of randomized controlled trials of RTX, it did not
significantly increase infection risk [57]. Two large observational studies also
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revealed that RTX was not associated with increased infection risk compared with
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reference biologic etanercept [58,59]. In a nearly 10-year long-term follow-up

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extended clinical trial, around 4% patients developed lower IgG level during RTX
treatment, and they also tended to have more comorbidities and higher risk of
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infection [60].
3.2.3. Abatacept (ABT)
A meta-analysis collecting 5 RCTs showed that abatacept was not associated with
increased infection risk (Odds ration [OR] 1.35, 0.78-2.32) [57]. Several other large
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observational studies also found that the infection risk posed by ABT was not higher
[56], or even lower [59,61], compared with other biologics. The 2015 ACR guideline
recommended abatacept instead of anti-TNF agents for patients with previous history
of serious infection [62].
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3.2.4. Tocilizumab (TOZ)
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A Meta-analysis of RCTs studies on TOZ showed no increased infection risk
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associated with its use [63]. As for other similar observational studies, some did not
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find significantly higher infection risk compared with other biologics [56,59,61], but
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another one did show relatively increased infection risk [58].
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3.2.5 Secukinumab (SCK)
Interleukin (IL)-17A is a proinflammatory cytokine with a central role in AS

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pathogenesis. From a long-term extension of SCK, the serious infection risk around
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0.6-1.1% person-year (PY), which was comparable with other biologic agents [64].
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3.2.6 Ustekinumab (UTK)
Ustekinumab, a human monoclonal antibody targeting the p40-subunit of interleukin

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(IL)-12 and IL-23, is indicated for moderate to psoriatic arthritis and plaque psoriasis.
From a large registry data including psoriatic patients, the incidence of serious
infection was 0.93% for UTK group. Although the incidence was numerically lower
compared with infliximab (2.91/100PY) and other biologics (1.91/100PY), it needed
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further data to investigate the accurate risk [65].
3.2.7 Biosimilars
The most common infection complication of anti-TNF biosimilar were respiratory
infection and urinary tract infection. The infection risk between biosimilar and
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reference drug seem no significant difference according to present limited data [66].
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3.3. The tsDMARDs
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3.3.1. Oral Janus kinase (JAK) inhibitor: tofacitinib
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From a large study from claim database, the incidence of serious infection of
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tofacitinib was 3.7% PY. After multivariable adjustment, infection risk was still higher
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(1.81, 95% CI 1.08-3.01) than no treatment group [67].
3.3.2. Oral phosphodiesterase 4 inhibitor: apremilast

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The data available on infection with apremilast usage were limited. According to
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long-term extension study, the risk of serious infection was comparable with reference
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group. However, this need more large study to investigate infection risk [68].
4. Data on the risk of tuberculosis (TB) associated with csDMARDs, bDMARDs,

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TB, Mycobacterium tuberculosis infection, remains a major global health problem,
and so does LTBI [69]. Although significant progress has been made toward the
elimination of TB, it is still a leading cause of morbidity and mortality worldwide.
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The elimination for TB relies on early case-finding, effective infection control
measures, and prevention of LTBI reactivation [69-71]. Increased risk of TB in RA
patients has been reported in Canada, Europe [72,73], and Asia [16,17]. In a
nationwide population-based cohort study, we revealed a significantly higher risk of
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TB and a greater mortality rates after TB diagnosis in RA patients when compared
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with general population [17]. Advanced age (≥ 65 years), male gender, the use of
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corticosteroids, and the presence of comorbidities including diabetes mellitus (DM),
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chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD)
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were all significant risk factors for developing TB in the RA cohort [17].
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Increasing evidence indicates that the TB risk is further elevated in adult patients with
inflammatory arthritis treated with csDMARDs, bDMARDs, or tsDMARDs

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[21,22,26,74-79]. The guidelines have recommended effective LTBI screening and

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prophylactic anti-TB therapy in case of LTBI [80]. In real-world settings, we observed

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a higher prevalence of LTBI in RA patients compared with healthy controls and
increased active TB development in RA patients treated with long-term TNF-α

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inhibitors [81], and isoniazid prophylaxis could effectively reduce TB risk in
biologics-exposed patients [82]. However, the long therapeutic period and
hepatotoxicity are barriers to completing 6-9 months of daily isoniazid treatment [83],
the standard therapy for LTBI. Recently, the implementation of 3-month once-weekly
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isoniazid plus rifapentine (3HP) by directly observed therapy (DOT) has been proved
useful in increasing the treatment adherence and effective in preventing active TB
[84,85]. We are also the first to reveal that implementing 3HP regimen is feasible for
treating LTBI in RA patients receiving biologic therapy [86]. Although anti-TNF-α
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therapy in children with inflammatory arthritis is safe [87,88], follow-up every 6
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months with respect to TB is important.
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4.1. The csDMARDs
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Given that T-cell immunity and the phagocytic activities of macrophages are crucial
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defense mechanisms against mycobacterial infection [89], the immunosuppressive
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effect of csDMARDs may contribute to elevated TB risk in RA patients [72,74,78].

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Previous studies have shown an increased TB risk with the use of oral CS [78,79]. As
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revealed in a population-based cohort study, RA patients receiving CS had an elevated

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risk of TB [72]. Brode et al. also reported an increased TB risk in RA patients treated
with moderate to high dose of CS [75] (Table 2). In intermediate-high TB incidence

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countries, the risk of LTBI reactivation was significantly elevated in psoriasis or PsA
patients receiving CS therapy [77]. The CS may increase the risk of LTBI reactivation
through inhibition of lymphokine effects and monocyte chemotaxis, suppression of
the production of IL-1β and TNF-α, and an impairment of T-cell activation [90].
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As an anchor drug, MTX is recommended as the first choice of csDMARD for the
treatment of RA [62]. MTX exerts its anti-inflammatory and immunosuppressive
effect through inhibition of purine and pyrimidine synthesis, reduction of
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antigen-specific T-cell proliferation, and enhancement of extracellular adenosine [91].
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As shown in Table 2, a population-based cohort study in Canada revealed that the use
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of csDMARDs containing MTX was associated with an increased TB risk in RA
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patients [74]. Brassard et al. also demonstrated an increased risk of active TB in RA
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patients receiving MTX therapy [72]. However, there was another similar study which
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showed no significant increase of such risk [75]. In studies performed in intermediate
to high TB incidence countries, MTX therapy did not significantly increase TB risk in
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patients with psoriasis or PsA [77] (Table 2). The conflicting results may be related to
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different concomitant medications used in patients with inflammatory arthritis.

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LEF, an inhibitor of de-novo pyrimidine synthesis by selective suppression of

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dihydro-orotate dehydrogenase, effectively reduces progression of RA [92]. Given the
immunosuppressive effect of LEF, increased TB risk associated with LEF use was
revealed in cases reports and case series [93,94]. Similarly, previous studies also
indicated an elevated risk of TB in RA patients undergoing LEF therapy [72,75]
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(Table 2).
4.1.4. Hydroxychloroquine (HCQ), sulfasalazine (SSZ), and cyclosporine A (CsA)
HCQ seems to exert its immunomodulatory effect through an action on lysosomal and
altered antigen process, inhibition of autophagy as well as interferon-α production,
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and suppression of calcium signals in T-cell [95]. Although Brode et al. revealed an
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increased TB risk in RA patients receiving HCQ therapy [75], there were very limited
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data regarding the impact of HCQ on TB risks. The SSZ is a csDMARD commonly
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used to treat RA and PsA. The main mechanism of action is impairment of
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lymphocyte functions by inhibiting the folate-dependent enzymes and enhancing
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apoptosis of neutrophils and macrophage [96]. However, the risk of active TB was not
elevated in RA patients undergoing SSZ therapy [75] (Table 2). CsA is an

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immunosuppressant commonly used to treat inflammatory arthritis. Only a few

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studies examined the risk of TB in rheumatic patients receiving CsA therapy. Brassard
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et al. revealed no significant association between CsA use and TB risk in RA patients
[72]. Chen et al. also demonstrated no significant increase of TB risk in psoriasis/PsA

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patients treated with CsA even in an intermediate TB-endemic country [77].
4.2. The bDMARDs
Given the critical role of TNF-α in TB granuloma formation and maintenance [97,98],
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TNFi may disrupt TB granuloma and thus facilitate reactivation of TB infection [99].
Even in low-TB incidence countries like Canada or European countries, increasing
evidence from these countries indicates that the immunosuppressive effect of TNFi
contributes to elevated TB risk in RA patients [21,74,75,99], and the risk of active TB,
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particularly extra-pulmonary TB, is increased in inflammatory arthritis patients
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treated with TNFi [100-105]. Among TNF inhibitors (TNFi), monoclonal antibody
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TNFi was linked to higher TB risk than soluble receptor for TNF-α [106-108]. The
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meta-analysis studies also showed that monoclonal antibody TNFi, particularly IFX,
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posed a higher risk of LTBI reactivation compared with soluble receptor for TNF-α
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such as ETN in arthritis patients [109,110]. In intermediate to high TB incidence
countries, the TB risks further increased [17,111-116]. We also revealed a biphasic

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emergence of active TB in RA patients treated with TNFi, particularly monoclonal

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antibody TNFi, reactivation of LTBI in early phase and new TB infection in the late
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phase [117]. These observations suggest the importance of LTBI screening with
prophylactic therapy before starting TNFi therapy and close monitoring of emergence
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of TB in arthritis patients during the period of TNFi therapy [80,81,118].
4.2.2. Non-TNF biologics
Given the complex pathogenesis of RA, AS and PsA, several classes of biologics with
different mechanisms of action have been licensed for the treatment of these diseases.
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For non-TNFi biologics such as tocilizumab (interleukin-6 inhibitor), abatacept
(T-cell co-stimulator blocker), and rituximab (B-cell depletion agent), the associated
TB risk was reported to be relatively low compared with TNFi [119,120].
4.2.2.1. Tocilizumab (TOZ)
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The TOZ, a monoclonal antibody against IL-6 receptor, blocks the pro-inflammatory
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action of IL-6 by inhibiting its binding to receptor. Although IL-6 plays a role in TB
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granuloma maintenance, Ogata et al. reported minimal influence of TOZ on IFN-γ
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synthesis by tuberculosis antigens [121]. Cantini et al. reported no occurrence of
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active TB among RA patients in 30 clinical trials [26]. A post-marketing surveillance
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(PMS) revealed the emergence of active TB in four of 3881 patients treated with TOZ
in Japan [119], while no TB infection was found in the Japan Real registry of
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TOZ-treated patients [122]. The French REGATE registry [123] and the TOZURA
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worldwide phase 4 study [124] reported one TB patient each in 1491 and 1804
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TOZ-treated patients respectively. However, increased TB risk was observed in
TOZ-exposed RA patients in intermediate to high TB incidence countries [125].

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ABT binds to the CD80/CD86 costimulatory pathway of T-cell and thus blocks T-cell
activation. In low TB incidence countries, only three cases of active TB were
observed among ABT-treated RA patients in 17 clinical trials [125], and no TB case
20

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was found in the French RATIO registry [126], a Japan cohort study [127] or the PMS
of Japanese RA patients treated with ABT [128]. Similarly, no TB case was reported
among ABT-treated PsA patients in a phase III long-term extension study [129].
However, in the recent worldwide surveillance, 18 cases of active TB were found in
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ABT-treated RA patients in the intermediate to high TB incidence countries [125].
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4.2.4. Rituximab (RTX)
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RTX, an anti-CD20 monoclonal antibody, has been shown to be effective for RA
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patients with inadequate response to anti-TNF-α therapy. Given no significant effect
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of RTX therapy on the released IFN-γ levels in RA patients with LTBI [130], active
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TB has not been reported in RA patients receiving RTX therapy in clinical trials [7] or
in real-world practice [130], with only 3 cases of active TB reported in a survey

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conducted by the Emerging Infections Network (EIN) [131]. In a nationwide

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retrospective cohort study in Taiwan, only two TB cases were identified in 6,179
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RTX-exposed patient-years, with the TB risk significantly lower compared with the
csDMARDs-exposed group [82]. These observations support the long-term safety of

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RTX treatment for arthritis patients in terms of TB infection [132-134].
4.2.5. Secukinumab (SCK)
Secukinumab, a human monoclonal antibody directed against IL-17A, has been
shown to be effective in the treatment of moderate to severe AS, psoriasis, and PsA.
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Clinical observations show a low risk of TB reactivation upon secukinumab treatment
[135-137], which is further supported by the investigations showing lack of
compromised host resistance in anti-IL-17A-treated M. tuberculosis-infected mice
[138].
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4.2.6. Ustekinumab (UTK)
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Ustekinumab, an IL-12 and IL-23 inhibitor, has emerged as an effective therapeutic
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agent for psoriasis patients. Although there was no occurrence of active TB in
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worldwide 3474 patients treated with UTK [139], screening for LTBI before starting
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UTK treatment is needed.
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4.2.7. Biosimilars
The recent development of biosimilars may help reduce the cost of biologic treatment.
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As expected, clinical trials show comparable efficacy and safety between biosimilars
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and biologics with no clinically meaningful differences in terms of TB risks

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[140,141].
4.3. The tsDMARDs

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Tofacitinib, a preferential inhibitor for JAK3 and JAK1, is effective and well-tolerated
for the treatment of RA [11,142]. Based on phase II, III, and long-term extension
clinical trial data from tofacitinib-treated RA patients (n=5671), 26 developed active
22

23
TB [143]. Twenty-one cases (81%) occurred in countries with high background TB
infection and in patients using high dose of tofacitinib (10mg twice daily).
4.3.2. Oral phosphodiesterase 4 inhibitor: apremilast,
Apremilast, an oral phosphodiesterase 4 inhibitor, has been approved in the treatment
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of psoriasis patients. The results from clinical trials of apremilast for the treatment of
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psoriasis patients, no emergence of TB was reported [144,145].
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5. Data on the risk of HBV reactivation associated with csDMARDs, bDMARDs,
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Reduced immune control, caused by inhibition of tumor necrosis factor or depletion
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of B-cell for example, could facilitate HBV reactivation (HBVr), which could induce
active necrotizing hepatitis due to replication of HBV virus [146]. This occurs not
ed
only in HBsAg-positive (HBsAg+) patients, but also in HBsAg-negative anti-HBc

pt
antibodies-positive (HBsAg-/anti-HBc+) patients [147]. In the age of csDMARD,

ce
HBVr is important for HBsAg+ patients but relatively rare in HBsAg-/anti-HBc+
patients [148-154]. After the emergence of biological agents, more HBVr has been
Ac
noted in HBsAg-/anti-HBc+ patients, so the issue attracts more attention to both
HBsAg+ and HBsAg-/anti-HBc+ biologic users.
5.1. The csDMARDs
23

24
HBsAg+
In addition to large dose of steroids (such as steroid pulses) that could induce
fulminant hepatitis in HBsAg+ patients [155,156], long-term use of steroids at 15-20
mg/day also increased the susceptibility to hepatitis [157]. However, it has been
t
reported that low dose of steroids at 7.5 mg/day was less likely to cause HBVr in
ip
HBsAg+ patients [158].
cr
HBsAg-/anti-HBc+
us
There is a paucity of data on steroids use in HBsAg-/HBcAb+ patients. However,
an
HBsAg-/anti-HBcAb+ patients are considered as low-risk group (<1%) in terms of
M
developing HBVr during steroid treatment according to the 2015 American
Gastroenterological Association (AGA) Guidelines [159].

ed

pt
HBsAg+
ce
With direct hepatotoxicity of MTX, there had been several HBsAg+ patients who
developed fulminant viral hepatitis after discontinuation of MTX [160-163]. In a

Ac
clinical cohort study following 19 HBsAg+ patients who have taking MTX for two
years in Korea [164], the incidence of abnormal liver function among them was
higher compared with non-HBsAg positive patients (47% vs 7%). Besides, in half of
the HBsAg+ patients, the HBV DNA turn from negative to positive after using MTX.
24

25
HBsAg-/anti-HBc+
Although there had been a few cases reports of HBVr in HBsAg-/anti-HBc+ patients
using MTX [165-167], another large cohort study did not show HBVr in such patients
[168]. So the risk of HBVr seems rather low in this patient group [159].
t
5.1.3. Other non-biologics
ip
HBsAg+
cr
One study following 15 HBsAg+ patients using LEF found 29% of them developed
us
HBVr [169]. However, in most of such studies, patients were treated with a
an
combination of DMARDs, so it was difficult to estimate the real risk associated with
M
individual DMARDs. Several studies used multivariate analysis to explore the risk of
HBVr linked to individual DMARDs in HBsAg+ patients using combination

ed
DMARDs therapy. Long-term use of DMARD and combined use of more than 2
pt
DMARDs were the major risk factors [170,171]. It was implied that profound
ce
immunosuppressive effect may increase the risk of HBVr in non-biologic users.
HBsAg-/anti-HBc+
Ac
Both a cohort following 135 HBsAg-/anti-HBc+ patients using non-biologic
DMARDs and another cohort following 36 patients using LEF showed no HBVr in all
subjects [169,172]. However, there were still a few cases developed HBVr in another
2 cohorts. Those cases were found to concomitantly receive an intensive
25

26
immunosuppressive agent, such as cyclophosphamide pulse therapy [173]. Although
HBVr rarely occurs in HBsAg-/anti-HBc+ patients using non-biologic, they should
still be closely monitored when receiving concomitant intensive immunosuppressive
therapy.
t
5.2. The bDMARDs
ip
cr
HBsAg+
us
TNF is an important cytokine that inhibits HBV replication in infected hepatocytes
an
[174]. In the absence of prophylactic antiviral agents, 6.9 - 62.5% patients receiving
M
anti-TNF would develop HBVr (Table 3), and the HBVr most commonly occurred
within the first year of anti-TNF use [175]. With the use of antiviral prophylaxis, the
ed
incidence of HBVr has reduced to nearly 0%. Only a few HBsAb+ patients who had
pt
received antiviral prophylaxis still developed HBVr [176,177]. These patients were
ce
found to have used lamivudine for prophylaxis and the HBVr showed a YUMM
mutation. Therefore, when long-term antiviral prophylaxis is needed, it is

Ac
recommended to use low-resistance drugs such as entecavir or tenocovir.
HBsAg-/anti-HBc+
In 2007, there was a first case report of HBVr caused by anti-TNF agent [178]. Since
then, however, several cohort studies have showed inconsistent results of HBVr in
26

27
anti-TNF user with HBsAg-/anti-HBc+ (Table 3). A review which collected 468
anti-TNF user with HBsAg-/anti-HBc+ reported that the incidence of HBVr was only
1.7% [179]. Concomitant use with immunosuppressive agents or corticosteroids was
considered an important risk factor for developing HBVr [180]. In addition, pooled
t
data collected from psoriasis patients showed zero incidence of HBVr [181], probably
ip
because dermatologists less frequently use MTX or steroids in addition to anti-TNF.
cr
As found in several subsequent larger combined review studies, the incidence of
us
HBVr may be less than 1% [176,181].
an
5.2.2. B-cell depletion agent, rituximab (RTX)
M
HBsAg+
According to the data derived from lymphoma patients, chemotherapy regimen

ed
including RTX brought about up to 60% incidence of HBVr if administered without

pt
antiviral prophylaxis [159]. Since RTX is classified as a high-risk drug for HBVr in
ce
the rheumatology field [182], it is rarely used in HBsAg+ rheumatic patients, and
there was no related case-series or cohort studies available.

Ac
HBsAg-/anti-HBc+
Although the incidence of HBVr in HBsAg-/anti-HBcAb+ lymphoma patients
receiving RTX was as high as 23.8–41.5% [183], however, the incidence for RA
patients receiving RTX was much lower, around 0-9.1% [184-186]. The causes of the
27

28
differential incidence may include: the dose of RTX for RA patients is much lower
and the infusion frequency less intensive compared to the regimen used to treat
lymphoma; concomitant medications for RA patients had lesser immunosuppressive
and cytotoxic effects; the immune status of RA patients was different from that of
t
lymphoma patients [186]. Although the risk is relatively lower than in hematologic
ip
field, close monitoring is also suggested because there were still several cases of
cr
HBVr in RA patients.
us
an
HBsAg+
M
One study following 4 RA patients who used ABT without anti-viral prophylaxis
found that all four patients developed HBVr [187]. However, in another study which
ed
collected 38 RA patients using ABT without taking prophylactic antibiotics, none of

pt
the 38 patients developed HBVr [188]. It is not clear why these two studies have such
ce
different results, but different ethnicity, age, or HBeAb status may be part of the
causes.
Ac
HBsAg-/anti-HBc+
The only one study which collected 27 HBsAg-/anti-HBc+ RA patient treated with
ABT, of whom 19% receiving pre-emptive anti-viral agents, reported no case of
HBVr [189].
28

29
HBsAg+
The data about HBsAg+ patients receiving TOZ was very limited. Only a few cases
reports about such patients showed no risk of HBVr [189]. Cohort studies with larger
t
sample size would be needed to help understand the HBVr risk of associated with
ip
TOZ in HBsAg+ patients.
cr
HBsAg-/anti-HBc+
us
There had been a few cases reports showing transient low titer HBV viral load that
an
resolved spontaneously without anti-viral therapy in RA patients using TOZ [173,190].
M
In 2 small cohort studies enrolling a total of 12 cases using TOZ, no patient developed
HBVr [191,192]. In another large cohort study, only one (1/35, 3%) of the 35 patients
ed
treated with TOZ had been detected HBV DNA –positive, but whose level was lower
pt
than 2.1 log copies/mL [193] and turned to negative later without anti-viral therapy.
ce
5.2.5 Secukinumab (SCK)
HBsAg+
Ac
A cohort following 25 HBsAg+ patients using SCK, and 4 in 22 HBsAg+ patients
without receiving prophylactic antiviral therapy had HBV reactivation. And there was
no reactivation in other three HBsAg+ patients receiving prophylactic antiviral
therapy. So, monitor HBV reactivation in HBsAg+ patients using SCK should be
29

30
recommended [194].
HBsAg-/anti-HBc+
In 24 HBsAg-/anti-HBc+ patients using SCK, there had one patient had HBV
reactivation. And this patient had positive HBV DNA at baseline [194].
t
5.2.6 Ustekinumab (UTK)
ip
HBsAg+
cr
According to 2 large case series from Taiwan, 4 in 15 (26.6%) patients without
us
antiviral therapy had HBV reactivation, and none had HBV reactivation in 13 patients
an
receiving antiviral therapy [195,196]. Therefore, prophylactic antiviral therapy still
M
should be recommended in UTK user.
HBsAg-/anti-HBc+
ed
According to small case series and case reports, there had total 2 cases of HBV
pt
reactivation in 85 HBsAg-/anti-HBc+ patients [197]. Although the risk is relative low

ce
compare to HBsAg+, monitor HBV reactivation still should be recommended.
5.3. The tsDMARDs

Ac
From a cohort from Taiwan which following six HBsAg+ patients, 2 in 4 patients
without prophylactic therapy had HBV reactivation. The other 2 patients receiving
prophylactic therapy had no reactivation. Of 75 HBsAg-/anti-HBc+ patients, none had
30

31
HBV reactivation [198].
Only one case of HBsAg+ using apremilast was reported. This patient did not have
detectable HBV DNA at baseline and without prophylactic anti-viral therapy. After
t
one-year treatment of apremilast, the HBV DNA still was undetectable [197].
ip
6. Data on the risk of HCV reactivation associated with csDMARDs, bDMARDs,
cr
and tsDMARDs therapies for RA and PsA
us
HCV infection is a major health issue; the World Health Organization (WHO)
an
estimates that at least 170 million people, approximately 3% of the global population,
M
are chronically infected [199,200]. It was reported that 0.65-7.6% of RA patients had
concomitant HCV infection [201], which provides a therapeutic challenge because

ed
immunosuppressive therapy may promote viral reactivation. Despite recent advances

pt
in HCV eradication with direct-acting antiviral agents (DAAs), it remains prevalent

ce
worldwide and presents a major challenge to treatment of RA [201,202]. In addition,
HCV viral replication varies considerably in response to non-biologics or biologics

Ac
therapy owing to their different mechanisms of action in arthritis patients
[32,203-205].
6.1. The csDMARDs
31

32
Although high-dose CS may have the potential to enhance HCV infection and
increase HCV dissemination [206], there has not been any clinical study to confirm
the impact of CS on HCV infection in patients with inflammatory arthritis.
t
Given the potential hepatotoxicity of MTX, Kremer et al. recommend an investigation
ip
of HCV serology before starting MTX and regular monitoring of liver toxicity during
cr
MTX treatment for RA patients [207]. Despite MTX-related hepatotoxicity being an
us
important issue, there are limited data available about the safety of MTX use in RA
an
patients with concomitant HCV. Kujawska et al. revealed no occurrence of liver
M
cirrhosis in RA patients treated with MTX for 12 months [208]. This result was
consistent with the findings from a nationwide population-based study that MTX was
ed
not associated with significantly increased risk of liver cirrhosis in HCV-positive RA

pt
[209] or PsA patients [210]. In addition, Mok et al. demonstrated stable liver enzyme
ce
profiles and HCV viral loads in six MTX-treated HCV-positive patients [205].

Ac
Although the potential hepatotoxicity of LEF [211], no data are available regarding its
effect on HCV infection in patients with inflammatory arthritis. However, arthritis
patients would be screened for HCV infection before starting LEF therapy based on
the recommendations proposed by Kremer et al. [207]. In addition, LEF is not
32

33
recommended in the presence of hepatopathy with all Child-Pugh class [34].
6.1.4. Cyclosporine A (CsA)
CsA is a commonly used immunosuppressant to treat inflammatory arthritis. Previous
studies revealed that CsA exerted an inhibitory effect on HCV replication through
t
inhibition of cyclophilin B [212]. However, there has been limited data regarding the
ip
safety of CsA use in patients with concomitant HCV infection [213,214]. A recent
cr
study demonstrates no reactivation of HCV infection in 11 PsA patients undergoing
us
CsA therapy [213]. Galeazzi et al. further revealed decreases of HCV viral loads in 9
an
(60.8%) of 15 arthritis patients (11 RA and 4 PsA) receiving CsA therapy [214].
M
Therefore, the available data indicate that the use of CsA contributes to a better
outcome in arthritis patients with concomitant HCV infection. However, the safety of
ed
CsA use in HCV-positive arthritis patients will requires more prospective studies with
pt
larger sample size and longer follow-up to analyze virologic markers and hepatic
ce
histologic data.
6.2. The bDMARDs

Ac
In patients with chronic HCV infection, a predominance of type 2 T-helper (Th2) cell
inflammatory response has been observed [215]. TNF-α has been shown to impair the
proliferation of CD4 cells and inhibit the production of antigen-specific Th1 cells
33

34
[216]. Therefore, anti-TNF therapy may restore the production and function of Th1
cells, which explain the improved rates of viral eradication in patients with chronic
HCV infection [217]. Some studies have also demonstrated that TNFi may be safe to
use in patients with chronic HCV infection [32,218-222]. These observations support
t
the 2012 update of the 2008 ACR recommendations for the use of etanercept in RA
ip
patients with HCV infection [223]. A recent randomized clinical trial also showed that
cr
RA patients with chronic HCV were successfully treated by etanercept without
us
elevation of transaminases or HCV viral load [224]. Our results also showed that the
an
use of TNFi including etanercept, adalimumab or golimumab for more than 2 years
M
did not increase HCV viral replication [225]. In addition, the use of TNFi seemed to
be safe for PsA patients with concomitant HCV infection [226-228]. Given that there
ed
were still some cases reports and series revealing elevated liver enzyme or viral loads
pt
[229-233], the randomized control trials are needed to clarify the safety of TNFi for
ce
arthritis patients with HCV infection.

Ac
Because high levels of serum IL-6 in HCV-infected patients induce hepatic
inflammation, viral loads in HCV-infected RA patients have been reported to be
unaffected or even decline during short-term TOZ therapy [234-236]. Given the small
number of the reported cases, the safety of TOZ in arthritis patients with concomitant
34

35
HCV infection remains to be elucidated [237].
Although ABT has been shown to be safe for RA patients with HCV [236,238],
increased viral loads were found in two HCV-positive patients treated with ABT in
t
one study [239]. Interestingly, we found HCV viral loads decreased significantly after
ip
ABT treatment [236], consistent with a previous report showing that HCV RNA might
cr
become undetectable after costimulatory blockade [238]. RA patients may show
us
various states of T-cell exhaustion, which could be restored after ABT therapy, further
an
enhancing T cell functionality and suppressing viral replication [240]. Given that the
M
number of ABT-treated patients is limited, prospective long-term study which recruits
a larger number of HCV-infected RA patients is needed.

ed
6.2.4. Rituximab (RTX)

pt
Although some studies showed that RTX was an effective treatment for patients with
ce
HCV-associated cryoglobulinemic vasculitis without influencing HCV viremia [241],
increased HCV-RNA levels during or after RTX therapy had been reported in
Ac
HCV-positive patients with non-Hodgkin’s lymphoma [242] or in RA [225]. The
B-cell targeted therapy with rituximab may lead to HCV viremia by causing a decline
of exosomal microRNA-155 in RA patients [243]. Given that prolonged
immunosuppression could impair host immunity against HCV, the use of RTX is not
35

36
recommended for RA patients with HCV infection [244] or HCV-positive patients
with Child-Pugh class B-C hepatic impairment [34]. Frequent monitoring of HCV
viral loads in arthritis patients is highly suggested during the period of RTX treatment.
6.2.5. Secukinumab (SCK)
t
In a multicentric prospective cohort study (n=284), one of 14 psoriasis patients with
ip
concomitant HCV infection showed an enhanced viral replication with hepatitis [245].
cr
The use of SCK did not influence the antiviral effect of DAAs in psoriasis patient
us
with concomitant HCV infection [246].
an
6.2.6. Ustekinumab (UTK)
M
Three psoriasis patients who had concomitant HCV infection and received UTK
therapy did not exhibit aggravation of their hepatitis after a mean follow-up period of
ed
15 months [247]. However, one psoriasis patient with HCV, liver cirrhosis and treated
pt
hepatocellular carcinoma experienced HCV reactivation of HCV during the UTK

ce
treatment [248]. Therefore, the risk of HCV reactivation during UTK treatment may
exist and appropriate vigilance should be performed.

Ac
6.3. The tsDMARDs
In a hospital-based clinical data, nine RA patients with concomitant HCV infection
did not exhibit HCV reactivation [236]. Further study is needed to clarify whether the
36

37
inhibitors to different JAK family are safe in arthritis patients with HCV infection.
Limited data regarding the risk of hepatitis C viral reactivation in arthritis patients
with HCV infection during apremilast treatment. Reddy et al. reported a psoriasis
t
patient with combined infection with human immunodeficiency virus and HCV, no
ip
occurrence of HCV replication was found during 5-month apremilast therapy [249].
cr
7. Expert commentary
us
Both non-biologic and biologic DMARDs inevitably increase the risk of bacterial
an
infection. The risk associated with biologics is higher than with non-biologic. Given
M
that pneumonia is the leading bacterial infection, pneumococcus and influenza
vaccinations are strongly recommended for biologics users.

ed
The safety evidence gathered from RCTs, long-term extension studies, and
pt
post-marketing data indicates an increased TB risk in arthritis patients undergoing

ce
biologic therapy, particularly anti-TNF monoclonal antibodies, or in countries where
TB is endemic. Effective LTBI screening and prophylactic therapy would decrease the
Ac
risk of TB, particularly in patients with high risk of LTBI reactivation.
For HBsAg-positive patients receiving non-biologics, large dose of CS (such as pulse
therapy) and MTX would increase the risk of HBVr; as for other non-bioloigcs,
long-term use or combined use of more than two csDMARDs were also major risk
37

38
factors for HBVr. For HBsAg-negative/HBcAb-positive patients using non-biologics,
only profound immunosuppressive effect caused by intense treatment, such as
combined use with cyclophosphamide, can promote HBVr. For HBsAg-positive
patients, although plentiful data showed high risk of HBVr associated with TNFi
t
therapy, the risk can be effectively prevented by antiviral prophylaxis. For
ip
HBsAg-/HBcAb+ patients receiving TNFi, the combined therapy with DMARDs and
cr
CS seem to be the major risk factors. Although RTX poses the highest risk of HBVr
us
among all biologic in treating HBsAg-/HBcAb+ patients, the risk seems not as high as
an
in the field of hematologic treatment.
M
Based on the available evidence and the ACR guidelines for HCV-positive arthritis
patients [223], MTX or LEF should be cautiously used and HCV activity closely
ed
monitored. Although data regarding the safety of non-biologics or biologics for

pt
HCV-positive patients are limited, CsA, TNFi, TOZ, or ABT seem to be safe options
ce
of treatment. When rituximab is the preferred treatment, arthritis patients must be
closely followed up regarding HCV reactivation. Given the effectiveness of DAAs

Ac
therapy in the eradication of HCV [250], collaboration between rheumatologists and
hepatologists is suggested in the administration of direct antiviral therapy according to
the risk stratification.
38

39
Acknowledgements
The authors thank Shiow-Jiuan Wey, MD, of the Division of Dermatology,
Chung-Shan Medical University Hospital in Taiwan, for manuscript editing.
Funding
This paper was not funded.
t
ip
Declaration of interest
cr
The authors have no relevant affiliations or financial involvement with any
us
organization or entity with a financial interest in or financial conflict with the subject
matter or materials discussed in the manuscript. This includes employment,

an
consultancies, honoraria, stock ownership or options, expert testimony, grants or
M
patents received or pending, or royalties.

ed
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to

pt
disclose.
ce
Ac
39

40
Table 1. Available data regarding the risk of bacterial infection in inflammatory arthritis patients undergoing therapy with csDMARDs
or bDMARDs
Auther/ AD/ Study type Therapeutic Patient Concomitant F-U Safety outcome
t
Reference Country agents number medications period (Incidence or RR)
rip
Non-biologics (csDMARDs)
c
Pneumonia
us
Aletaha et al. [40] RA/Vienna Hospital-bas MTX 359 RA NA 1993-1999 Incidence 3.3%
es,
an
retrospective
Aletaha et al. [40] RA/Vienna Hospital-bas SSZ 267 RA NA 1993-1999 Incidence 1.9%
M
es,
retrospective
Dixon et al. [48] RA/UK BSRBR csDMARDs 1354 RA NA 2001-2005 Incidence 2.6%
d
registry
Wolfe et al. [41] RA/USA NDB
te
MTX, HCQ, 16788 RA NA 2001-2004 no CS = 1 (Ref)
ep
registry SSZ, LEF, CS CS = 1.7*
HCQ = 0.9
SSZ = 0.7
c
Ac
LEF = 1.2
MTX= 1.0
40

41
Bernatsky et al. RA/Canada Population-b MTX, HCQ, 23733 RA NA 1980-2003 no csDMARD = 1 (Ref)
[42] ases, claim CS, AZA, CS = 2.07*
data CTX MTX= 1.16*
t
HCQ = 1.06
rip
Smitten et al. RA/USA Population-b MTX, HCQ, 24530 RA NA 1999-2006 no csDMARD = 1 (Ref)
[18] ases, claim LEF, SSZ, CS CS(>10mg/day) = 2.98*
c
data CS(6-10mg/day)=1.94*
us
CS(<5mg/day)=1.32*
HCQ = 0.81
an
LEF = 1.02
SSZ=0.82
M
MTX= 0.81*
Grijalva et al. RA/USA Population-b MTX, HCQ, 14586 RA NA 1995-2005 MTX RR =1(Ref)
d
[50] ased, claim SSZ, LEF, CS CS(high dose) RR =
data
te 4.33*
CS(medium dose) RR =
ep
2.36*
CS(low dose) RR = 2.30*
c
HCQ RR = 1.24
Ac
SSZ RR = 0.60
LEF RR = 1.65
41

42
Kawashima et al. RA/Japan Hospital-bas MTX, SSZ 119 RA NA 2006-2012 Incidence 3.6%
[39] ed,
retrospective
t
Soft tissue / skin
rip
infection
Listing et al. [47] RA/German RABBIT All 601 RA NA 2001-2003 Incidence 0.35%
c
registry csDMARDs
us
registry
an
[39] ed
M
retrospective
Bone / joint
d
infection
Listing et al. [47] RA/German RABBIT All 601 RA NA 2001-2003 Incidence 0.18%
registry
te
csDMARDs
ep
registry
c
Ac
[39] ed,
retrospective
Pyelonephritis
Aletaha et al. [40] RA/Vienna Hospital-bas MTX 359 RA NA 1993-1999 Incidence 3.7%
42

43
es,
retrospective
Aletaha et al. [40] RA/Vienna Hospital-bas HCQ 285 RA NA 1993-1999 Incidence 0.7%
t
es,
rip
retrospective
Aletaha et al. [40] RA/Vienna Hospital-bas SSZ 267 RA NA 1993-1999 Incidence 1.9%
c
es,
us
retrospective
Aletaha et al. [40] RA/Vienna Hospital-bas CsA 31 RA NA 1993-1999 Incidence 7.3%
an
es,
retrospective
M
registry
d
[39] ed,
retrospective
te
ep
bDMARDs
Pneumonia
c
Listing et al. [47] RA/German RABBIT TNFi 858 RA csDMARDs 2001-2003 1.86-3.38%
Ac
registry
Dixon et al. [48] RA/UK BSRBR TNFi 7664 RA NA 2001-2005 2.1%
registry
43

44
Favalli et al. RA/Italy LORHEN TNFi 1064 RA MTX, CS 1999- 2002 0.47-1.42%
[101] registry
van Dartel et al. RA/Dutch DREAM TNFi 2356 RA MTX, CS 2003-2008 0.9-3.4%
t
[51] registry
rip
Yun et al. [61] RA/USA Population-b TNFi, RTX, 23784 RA MTX, CS, NSAID 2006-2011 1.88-4.89%
ased, claims ABT TOZ
c
data
us
Kawashima et al. RA/Japan Hospital-bas TNFi, TOZ 64 RA MTX, SSZ, CS 2006-2012 3.7%
[39] ed
an
retrospective
Rutherford et al. RA/UK BSRBR TNFi, RTX, 19282 RA MTX, LEF, SSZ, 2001-2016 1.72-3.16%
M
[57] registry TOZ, HCQ
Harrold et al.[52] RA/USA CORRONA TNFi, 6215 RA csDMARDs 2009-2010 1.25-1.78%
d
registry
Carrara et al.[58] RA/Italy Population-b TNFi, ABT, 4656 RA NSAIDs, MTX, 2004-2013 2.95 %
ased,
te
RTX, TOZ LEF, CsA, HCQ,
ep
claim data SSZ, CS
Aygun et al [28] JIA/Turkey Hospital-bas TNFi, TOZ, 307 JIA NSAIDs, MTX, 2017 1.0-15.3%
c
ed, ANA, CAN LEF, CsA, SSZ

Ac
prospective
Bacteremia
44

45
Carrara et al.[58] RA/Italy Population-b TNFi, ABT, 4656 RA NSAIDs, MTX, 2004-2013 2.51 (1.88-3.29)
ased, RTX, TOZ LEF, CsA, HCQ,
claim data SSZ, CS
t
Rutherford et RA/UK BSRBR TNFi, RTX, 19282 RA MTX, LEF, SSZ, 2001-2016 0.12-0.44 %
rip
al.[57] registry TOZ HCQ
c
ased, claims ABT, TOZ
us
data
Soft tissue/skin infection
an
Listing et al. [47] RA/German RABBIT TNFi 858 RA csDMARDs 2001-2003 1.23-1.45%
registry
M
Dixon et al. [48] RA/UK BSRBR TNFi 7664 RA NA 2001-2005 1.2 %
registry
d
Favalli et al. RA/Italy LORHEN TNFi 1064 RA MTX, CS 1999- 2002 0.23-1.02 %
[101] registry
van Dartel et al. RA/Dutch DREAM
te
TNFi 2356 RA MTX, CS 2003-2008 1.29-5.21%
ep
[51] registry
c

Ac
data
Kawashima et al. RA/Japan Hospital-bas TNFi, TOZ 64 RA MTX, SSZ, CS 2006-2012 1.9 %
[39] ed
retrospective
45

46
Rutherford et al. RA/UK BSRBR TNFi, RTX, 19282 RA MTX, LEF, SSZ, 2001-2016 0.42-1.38%
Harrold et al. [52] RA/USA CORRONA TNFi, 6215 RA csDMARDs 2009-2010 0.77-1.55 %
t
registry
rip
ased, claim RTX, TOZ LEF, CsA, HCQ,
c
data SSZ, CS
us
an
prospective
Bone/joint infection
M
Listing et al. [47] RA/German RABBIT TNFi 858 RA csDMARDs 2001-2003 0.31-1.03 %
registry
d
registry
van Dartel et al. RA/Dutch DREAM
te
TNFi 2356 RA MTX, CS 2003-2008 0.31-0.81 %
ep
[51] registry
Rutherford et al. RA/UK BSRBR TNFi, RTX, 19282 RA MTX, LEF, SSZ, 2001-2016 0.43-0.67 %
c

Ac
ased, RTX, TOZ LEF, CsA, HCQ,
claim data SSZ, CS
Pyelonephritis
46

47

registry
Favalli et al. RA/Italy LORHEN TNFi 1064 RA MTX, CS 1999- 2002 0-0.47 %
t
[101] registry
rip
van Dartel et al. RA/Dutch DREAM TNFi 2356 RA MTX, CS 2003-2008 0.13-0.48 %
[51] registry
c
Yun et al. [61] RA/USA Population-b TNFi, RTX, 23784 RA MTX, CS, NSAID 2006-2011 1.49-2.92 %
us
data
an
Kawashima et al. RA/Japan Hospital-bas TNFi, TOZ 64 RA MTX, SSZ, CS 2006-2012 0.65 %
[39] ed
M
retrospective
Rutherford et al. RA/UK BSRBR TNFi, RTX, 19282 RA MTX, LEF, SSZ, 2001-2016 0.36-0.81 %
d
Harrold et al. [52] RA/USA CORRONA TNFi, 6215 RA csDMARDs 2009-2010 0.62-1.19 %
registry
te
ep
c
data SSZ, CS
Ac
prospective
47

48
Meningitis / encephalitis
Harrold et al. [52] RA/USA CORRONA TNFi, 6215 RA csDMARDs 2009-2010 0-0.04 %
registry
t
rip
data SSZ, CS
c
Carrara et al. [58] RA/Italy Population-b TNFi, ABT, 4656 RA NSAIDs, MTX, 2004-2013 0.14 %
us
data SSZ, CS
an
Endocarditis
M
[51] registry
Carrara et al. [58] RA/Italy Population-b TNFi, ABT, 4656 RA NSAIDs, MTX, 2004-2013 0.14 %
d
Intro-abdominal
data
te SSZ, CS
ep
Favalli et al. RA/Italy LORHEN TNFi 1064 RA MTX, CS 1999- 2002 0.19-0.57 %
[101] registry
c
Ac
[51] registry
Rutherford et RA/UK BSRBR TNFi, RTX, 19282 RA MTX, LEF, SSZ, 2001-2016 0.18-0.76 %
al.[57] registry TOZ HCQ
48

49
csDMARD, conventional synthetic disease-modified anti-rheumatic drug; bDMARD, biologic disease-modified anti-rheumatic drug; NSAIDs,
non-steroidal anti-inflammatory drugs; JIA, juvenile idiopathic arthritis; F-U, follow-up; MTX, methotrexate; LEF, leflunomide; SSZ,
t
rip
salazopyrine; CsA, cyclosporine; HCQ, hydroxychloquine; CS, corticosteroids; RR, relative risk; TNFi, Tumor necrosis factor inhibitor; ABT,
c
us
abatacept; RTX, rituximab; TOZ, tocilizimab; ANA, anakinra; CAN, Canakinumab; NA, not available; RR, relative risk; *, p<0.05.
an
M
d
te
c ep
Ac
49

50
Table 2. Available data regarding the risk of reactivation of latent tuberculosis infection (LTBI) in inflammatory arthritis patients
undergoing therapy with csDMARDs or bDMARDs
Author/ Therapeutic Patients Concomitant F-U Safety
AD/Country Study type
t
Reference agents number medications period outcome
rip
Low TB incidence countries: Non-biologics (csDMARDs)
NSAIDs,
c
Brassard et al.[72] RA/Canada Cohort study, Retro. CS 24282/RA 1992-2003 RR of TB [2.4 (1.1-5.4)]
csDMARDs
us
CS NSAIDs, RR of TB [0.7 (0.5-1.1)]
Population-based
Brode et al.[75] RA/Canada <10mg/day 56269/RA csDMARDs, 2001-2011 RR of TB [1.7 (0.99-2.78)]
Case-control study
≧10mg/day TNFi RR of TB [1.6 (1.02-2.52)
an
Brassard et al.[72] RA/Canada Cohort study, Retro. csDMARDs 24282/RA NSAIDs,CS 1992-2003 RR of TB [3.0 (1.6-5.8)]
Population-based,
Brassard et al.[74] RA/Canada csDMARDs 112300/RA TNFi 1998-2003 RR of TB [1.4 (1.1-1.8)]
M
cohort study, Retro.
Population-based
Brode et al.[75] RA/Canada HCQ 56269/RA NSAIDs, TNFi 2001-2011 RR of TB [1.62 (1.1-2.3)]
Case-control study
d
Population-based
Brode et al.[75] RA/Canada SSZ 56269/RA NSAIDs, TNFi 2001-2011 RR of TB [0.89 (0.4-1.8)]
Brassard et al.[72] RA/Canada

te
Case-control study
Cohort study, Retro. LEF 24282/RA NSAIDs, CS 1992-2003 RR of TB [11.7 (2.1-65.1)]
ep
Population-based
Brode et al.[75] RA/Canada LEF 52269/RA NSAIDs, TNFi 2001-2011 RR of TB [2.74 (1.6-4.7)]
Case-control study
Brassard et al.[72] RA/Canada Cohort study, Retro. MTX 24282/RA NSAIDs, CS 1992-2003 RR of TB [3.4 (1.8-6.4)]
c
Ac
Population-based
Brode et al.[75] RA/Canada MTX 56269/RA NSAIDs, TNFi 2001-2011 RR of TB [1.3 (0.93-1.86)]
Case-control study
Brassard et al.[72] RA/Canada Cohort study, Retro. CsA 24282/RA NSAIDs, CS 1992-2003 RR of TB [3.8 (0.9-16.6)]
Intermediate-high TB incidence countries: Non-biologics (csDMARDs)
50

51
PsO-PsA/ Population-based 81266/ NSAIDs,

Chen et al.[77] CS 1996-2008 RR of TB [3.0 (2.2-4.1)]
Taiwan cohort study PsO-PsA csDMARDs
PsO-PsA/ Population-based 81266/
Chen et al.[77] MTX NSAIDs, CS 1996-2008 RR of TB [1.6 (0.6-4.1)]
Taiwan Retrospective PsO-PsA
t
rip
Low TB incidence countries: bDMARDs (TNF inhibitors)
Population-based NSAIDs,
Brode et al.[75] RA/Canada TNFi 56269/RA 2001-2011 RR of TB [2.2 (1.1-4.4)]
Case-control study csDMARDs
c
Population-based,
Brassard et al.[74] RA/Canada Infliximab 112300/RA csDMARDs 1998-2003 RR of TB [1.8 (1.1-3.0)]
us
Population-based,
Brassard et al.[74] RA/Canada Etanercept 112300/RA csDMARDs 1998-2003 RR of TB [1.3 (0.9-2.0)]
an
Gómez-Reino et al. Population-based 1265/RA NSAIDs, CS, 2000-2002 TB(17)/1138 IFX (15/RA,
RA/Spain IFX, ETN
[99] BIOBADASER 89/PsA MTX (12 months) 2/PsA); TB(0)/186ETN
NSAIDs, CS, 2001-2003 TB (1)/346 IFX
Listing et al.[46] RA/Germany RABBIT trial IFX, ETN 858/RA
M
csDMARDs (12 months) TB (0)/512 ETN
TB (4)/453 IFX
Gómez-Reino et al. Population-based IFX, ETN, NSAIDs, CS, 2003-2006
RA/Spain 1665/RA TB (1)/670 ETN
d
[99] BIOBADASER ADA MTX (12 months)
TB(1) /542 ADA
Takeuchi et al[100] RA/Japan PMS (IFX) te IFX 5000/RA
NSAIDs, CS,
MTX
2003-2004
(6 months)
TB (14)/5000 IFX
TB (3)/519 IFX
ep
Population-based IFX, ETN, NSAIDs, CS,
Favalli et al. [101] RA/Italy 1064/RA 36 months TB (1)/242 ETN
LOHREN ADA csDMARDs
TB (1)/303 ADA
c
TB (6)/837 IFX
Atzeni et al. [103] RA/Italy 2769/RA 108 months TB (1)/1130 ETN
Ac
GISEA ADA csDMARDs

TB (2)/802 ADA
TB (11)/3295 IFX
Dixon et al. [104] RA/UK 10712/RA 2003-2006 TB (5)/3913 ETN
BSRBR ADA csDMARDs
TB (11)/3504 ADA
51

52
TB (8)/2778 IFX
Winthrop et al. Pharmacy records IFX, ETN, NSAIDs, CS,
RA/USA 10429/RA 2000-2008 TB (8)/5320 ETN
[105] Cohort study, Retro. ADA csDMARDs
TB (7)/2331 ADA
Watanabe et al. NSAIDs, CS,
RA/Japan PMS (ADA) ADA 7755/RA 2008-2011 TB (22)/7755 ADA
t
[107] csDMARDs
rip
NSAIDs, CS, 2005-2007
Koike et al. [108] RA/Japan PMS (ETN) ETN 7091/RA TB(10)/7091 ETN
csDMARDs (6 months)
c
Intermediate-high TB incidence countries: bDMARDs (TNF inhibitors)
us
Retrospective NSAIDs, CS, TB (4)/484 ETN
Ke et al. [111] RA/Taiwan ETN, ADA 829/RA 2006-2008
Cohort study csDMARDs TB (5)/345 ADA
TB (2)/78 IFX
RA/South Population-based IFX, ETN, NSAIDs, CS,
an
Seong et al. [112] 354/RA 2001-2004 TB (0)/210 ETN
Korea Cohort study ADA csDMARDs
TB (1)/66 ADA
TB (1)/293 IFX
Yonekura et al. Population-based IFX, ETN, NSAIDs, CS,
M
RA/Brazil 942/RA 2009-2013 TB (1)/283 ETN
[113] BIOBADABRASIL ADA csDMARDs
TB (3)/366 ADA
Population-based NSAIDs, CS, TB(121)/3577 ETN
d
Liao et al. [17] RA/Taiwan ETN, ADA 5255/RA 2001-2011
Cohort study csDMARDs TB(67)/1678 ADA
Pharmaceutical
te
Low TB incidence countries: bDMARDs (Non-TNF biologics)
NSAIDs, CS,
ep
Cantini et al.[125] RA/worldwide TOZ 15485/RA NA TB(0)/Low TB area
companies (2018) csDMARDs
NSAIDs, CS,
Koike et al.[119] RA/Japan PMS (TOZ) TOZ 3881/RA 7 months TB(4)/3881 TOZ
csDMARDs
c
Registry
Sakai et al.[122] RA/Japan TOZ 302/RA NSAIDs, CS 2008-2011 TB(0)/302 TOZ
Ac
REAL
Registry
Morel et al.[123] RA/France TOZ 1491/RA NSAIDs, CS 2011-2015 TB(1)/1491 TOZ
REGATE
Choy et al.[124] RA/worldwide Phase 4 study TOZ 1804/RA csDMARDs >6 months TB(0)/353 monotherapy
52

53
TOZURA (353monotherapy) TB(1)/1451 combined Rx

Pharmaceutical NSAIDs, CS, TB(3)/Low TB area
Cantini et al.[125] RA/worldwide ABT 13394/RA NA
companies csDMARDs (Unknown No. of ABT)
NSAIDs, CS,
t
Mariette et al.[126] RA/France Registry ORA ABT 682/RA 8 months TB(0)/682 ABT
rip
csDMARDs
Takahashi et al. Cohort study NSAIDs, CS,
RA/Japan ABT 231/RA 6 months TB(0)/231 ABT
[127] Retrospective MTX (48.5%)
c
NSAIDs, CS,
Harigai et al.[128] RA/Japan PMS (ABT) ABT 3882/RA 2010-2011 TB(0)/3882 ABT
us
csDMARDs
Phase III extension
PsA/ NSAIDs, 2013-2015
Mease et al.[129] long-term study ABT 213/PsA TB(0)/213 ABT
worldwide csDMARDs (24 months)
an
van Vollenhoven et Global clinical trial NSAIDs, CS,
RA/worldwide RTX 3194/RA 9.5 years TB(2)/3194 RTX
al.[132] Long-term study csDMARDs
M
6 years
Prospective NSAIDs, CS,
Wendler et al.[133] RA/Germany RTX 2484/RA (median 14.7 TB(1)/2484 RTX
GERINIS csDMARDs
months)
d
Vassilopoulos et Prospective NSAIDs, CS,
RA/Greece RTX 234/RA 27.7 months TB(0)/234 RTX
al.[134] Cohort study
te
Intermediate-high TB incidence countries: bDMARDs (Non-TNF biologics)
csDMARDs
ep
Pharmaceutical NSAIDs, CS, TB (12)/Unknown No. of
Cantini et al.[125] RA/worldwide TOZ 22661/RA NA
companies (2018) csDMARDs TOZ
TB(18)/Intermediate/high
c
Pharmaceutical NSAIDs, CS,

Cantini et al.[125] RA/worldwide ABT 13394/RA NA TB area (Unknown No. of
companies (2018) csDMARDs
Ac
ABT)
Prospective NSAIDs, CS,
Chen et al.[130] RA/Taiwan RTX 56/RA 12 months TB(0)/56 RTX
Cohort study csDMARDs
Liao et al.[82] RA/Taiwan Population-based RTX 763/RA NSAIDs, CS, 2001-2011 TB(2)/763 RTX
53

54
Retrospective csDMARDs
csDMARDs: conventional synthetic disease-modifying anti-rheumatic drugs; bDMARD, biologic disease-modified anti-rheumatic drug; AD:
t
rip
autoimmune diseases; RA: rheumatoid arthritis; PsA: psoriatic arthritis; F-U: follow-up; NSAIDs: non-steroidal anti-inflammatory drugs; CS:
c
corticosteroids; MTX: methotrexate; CsA: cyclosporine A; HCQ: hydroxychloroquine; SSZ: sulfasalazine; LEF: lefluomide; TNFi: tumor
us
necrosis factor inhibitors; ETN: etanercept; IFX: infliximab; ADA: adalimumab; GOL: golimumab; TOZ: tocilizumab; ABT: abatacept; RTX:
an
rituximab; NA: not available.
M
d
Table 3. Available data regarding the risk of HBV reactivation inflammatory arthritis patients undergoing therapy with csDMARDs
or bDMARDs
Author/ AD/Country Study
te Therapeutic Patient Concomitant F-U HBV Prophylactic
ep
Reference type agents number medication period reactivation antiviral
c
Non-biologics (csDMARDs)
Ac
HBsAg+
54

55
Park et al. RA/Korea Cohort MTX 19 SSZ, HCQ 24M 50% No

2001[164]
t
rip
Tan et al. RA/China Cohort csDMARD 23 CS 20M 8.7% No
[148]
c
us
Ming-Xu et RA/China Cohort LEF 15 NA 2-85M 29% No
al.[169]
an
Mo et al. RA/China Case MTX, 6 CS NA 44% No
[149] series LEF,HCQ, SSZ
M
Tan et al. RA/China Case csDMARD 4 CS 20M 0 Yes
[148] series
d
Mo et al. RA/China Cohort 10 CS NA 2/11 Yes
[149]
HBsAg-/HBcAb+
te
ep
Laohapand et RA-others/Thailand Cohort MTX 65 NA 9.9yrs 0% No
al. [168]
c
Urata et RA/Japan Cohort csDMARD 135 TNFi, TOC, 12M 0% No

Ac
al.[172] RTX, CS
Ming-Xu et al. RA/China Cohort LEF 36 NA 2-85M 0% No
[169]
55

56
Kato et RA-others/Japan Cohort csDMARD 35 CTX 2-31M 5.7% No

al.[173]
Tan et al. RA/China Cohort csDMARD 188 CS 20M 1.1% No
t
[148]
rip
bDMARDs
c
HBsAg+
us
Lan et al.[23] RA/Taiwan Cohort TNFi 8 MTX, CS, 12M 62.5% No
csDMARD
an
Ryu et al. RA-SpA/Korea Cohort TNFi 29 MTX, SSZ, 12M 6.9% No
[176] HCQ, LEF
M
Kim et al. RA/USA Case ABT 4 MTX, SSZ, 3-33M 100% No
[187] series HCQ, LEF, CS
d
Cho et PsO-PsA/Taiwan Case TNFi 6 NA 14-45M 50% No
al.[150]
Jung et al. RA-SpA/Japan
te
series
Cohort TNFi 23 csDMARD NA 18.8% No
ep
[177]
Ye et al.[151] RA-PsA-SP/China Cohort TNFi 24 csDMARD 9-22M 33% No
c
Padovan et al. RA/Italy Cohort ABT 38 csDMARD 24M 0% No

Ac
[188]
Vassilopoulos RA-SpA/Greece Cohort TNFi 14 MTX, CS, 24M 0% Yes
et al.[152] csDMARD
56

57
Lan et al. [23] RA/Taiwan Cohort TNFi 10 MTX, CS, 12M 0% Yes
csDMARD
Cho et al. PsO-PsA/Taiwan Case TNFi 1 NA 14-45M 0% Yes
t
[150] series
rip
Kim et al. RA/USA Case ABT 4 MTX, SSZ, 3-33M 0% Yes
[187] series HCQ, LEF, CS
c
Ryu et al. RA-SpA/Korea Cohort TNFi 20 MTX, SSZ, 12M 5% Yes
us
[176] HCQ, LEF
Jung et RA-SpA/Japan Cohort TNFi 23 csDMARDs NA 14% Yes
an
al.[177]
Ye et al. [151] RA-PsA-SpA/China Cohort TNFi 13 csDMARD 9-22M 0% Yes
M
Padovan et al. RA/Italy Cohort ABT 13 csDMARD 24M 0% Yes
[188]
d
HBsAg-/HBcAb+
Vassilopoulos
et al.[152]
RA-SpA/ Greece
te
Cohort TNFi 19 MTX,
csDMARD, CS
24M 0% No
ep
Urata et RA/Japan Cohort TNFi, TOZ 52 MTX, CS 12M 5% No
al.[172]
c
Tamori et RA/Japan Cohort TNFi 45 MTX, 23M 2% No

Ac
al[165] csDMARD, CS
Mori [191] RA/Japan Cohort TNFi, TOZ 36 MTX, LEF, CS NA 2.8% No
Lan et al. [23] RA/Taiwan Cohort TNFi 12 MTX, NA 8% No
57

58
csDMARD, CS
Mitroulis et RA/Greece Cohort RTX 12 MTX, 13M 0% No
al.[184] csDMARD, CS
t
Ye et al. [151] RA-PsA-SPA/China Cohort TNFi 50 NA 12M 0% No
rip
Barone et al. RA-PsA-SPA-others/Italy Cohort TNFi, TOZ, 179 csDMARD 17-55M 0% No
[192] ABT, RTX,
c
IL1RA
us
Nakamura et RA/Japan Cohort TNFi, TOZ, 57 MTX,SSZ, CsA 18M 5.3% No
al. [190] ABT
an
Varisco et RA/Italy Cohort RTX 33 MTX,SSZ, CsA, 34M 3% No
al.[185] LEF, CS
M
Padovan et al. RA/Italy Cohort ABT 21 MTX,SSZ, 24M 0% In 19% p’t
[188] HCQ, LEF, CS
d
Giannitt et al. SpA/Italy Cohort TNFi 131 NA 75.5M 0% No
[153]
Fukuda et RA/Japan
te
Cohort TNFi, TOZ, 915 MTX 12-24M 3.5% No
ep
al.[193] ABT
Tien et al. RA/Taiwan Cohort RTX 44 csDMARD 26M 9.1% No
c
[186]
Ac
Matsuzaki et RA/Japan Cohort Biologic 360 MTX, LEF, SSZ NA 1.7% No

al. [154] DMARD/
csDMARD
58

59
csDMARD, conventional synthetic disease-modified anti-rheumatic drug; bDMARD, biologic disease-modified anti-rheumatic drug; F-U:
follow-up; MTX, methotrexate; LEF, leflunomide; CTX, cyclophosphamide; CsA, cyclosporine; TNFi, Tumor necrosis factor inhibitor; ABT,
t
rip
abatacept; RTX, rituximab; TOZ, tocilizimab; NA, not available
c
us
Table 4. Available data regarding the risk of reactivation of hepatitis C virus (HCV) infection in inflammatory arthritis patients
an
undergoing therapy with non-biologics (csDMARDs) or bDMARDs
M
Author/ Therapeut. Patients Concomitant F-U
AD/Country Study type Outcome
Reference agents number medications period
Population-based 1997-2011
d
Burton et al [203] RA/USA csDMARDs 748/RA NSAIDs,CS Elevated ALT: 2.3%
Cohort study (12 months)
Kujawska et al.[208] RA/USA
Population-based
retrospective
te MTX 71/RA NSAIDs, CS 12 months
Liver biopsy (3) showed
no cirrhosis
ep
Population-based No increase of liver
Tang et al [209] RA/Taiwan MTX 255/RA NSAIDs, CS 5 years
Cohort study cirrhosis
Population-based 174/PsO or No increase of liver
Tang et al [210] PsO-PsA/Taiwan MTX None 9 years
c
Cohort study PsA cirrhosis

Ac
Mok et al [205] RA/Hong Kong Cohort study MTX 6/RA NSAIDs, CS 1.9 years Stable ALT & viral loads
11/RA, Decreased ALT (21.6%)
Galeazzi et al [214] RA, PsA/Italy Prospective CsA CS, TNFi 6 months
4 /PsA and viral loads (60.8%)
59

60
Prospective
Colombo et al [213] PsA/Italy observational study CsA 11/PsA NSAIDs 12 months Stable ALT & viral loads
(SYNERGY)
Population-based 1997-2011
Burton et al [203] RA/USA Biologics 748/RA CS,csDMARDs Elevated ALT: 4.8%
t
Cohort study (12 months)
rip
NSAIDs(17),
9 months Decreased viral loads
Peterson et al [219] RA/USA Cohort study ETN, IFX 24/RA MTX(3),
(Mean) (66.7%)
HCQ+MTX(1)
c
No elevation ALT
Parke et al [220] RA/USA Cases report ETN, IFX 5/RA NA 41 months
us
Decreased viral load (1)
Vauloup et al [221] RA/France Case series ETN, IFX 6/RA MTX (6) 3.5 months Stable ALT & viral loads
an
Roux et al [222] RA/France Cases report ETN, ADA 3/RA MTX (2) 21 months Stable ALT & viral loads
Prospective, MTX, ETN, MTX alone (9)
Iannone et al [224] RA/Italy 29/RA 12 months Stable ALT & viral loads
M
randomized trial ETN+MTX MTX+ETN (7)
MTX (6),
Retrospective ETN, ADA, 23.4±13.7
Chen et al [225] RA/Taiwan 20/RA HCQ(13) Stable ALT & viral loads
Cohort study GOL months
d
SSZ (3)
Cavazzana [226]
Magliocco et al[227] PsA/USA
RA,PsA/Italy
te
Case series
Cases report
ETN
ETN
4/RA, 1/PsA HCQ(3),SSZ(1)
2/PsA None
14 months
5 months
Stable ALT & viral loads
Stable ALT & viral loads
ep
Costa et al [228] PsA/Italy Prospective ETN, ADA 15/PsA None 16 months Stable ALT & viral loads
Elevated ALT (1/ETN)
c
ETN, IFX,
Ferri et al [229] RA/Italy Cohort study 31/RA CS(31),MTX(1) 20 months Elevated viral loads
ADA
Ac
(1/ETN, 2/IFX)
ETN, IFX, HCQ(3),SSZ(4) 20±16 Elevated viral loads
Li et al [230] RA/USA Case series 8/RA
ADA MTX(2) months (1/IFX)
Elevated ALT in 2 patients
Lin et al [231] RA/Taiwan Case series ETN, ADA 20/RA CS, MTX 11 months
No checking viral loads
60

61
Elevated γGT with

Frider et al [232] RA/Argentina One case report ADA 1/RA None 3 months
interface hepatitis (biopsy)
Retrospective Biologic Elevated ALT (7)
Gandhi et al [233] RA,PsA/USA ETN csDMARDs 105 months
Cohort study naive Elevated viral loads (2)
t
Dragonas et al [234] RA/Germany One case report TOZ TNFi failure None 12 months Stable ALT & viral loads
rip
Decreased ALT and viral
Giannitti et al [235] RA/Italy One case report TOZ TNFi failure CsA 12 months
loads compared to baseline
c
MTX(1),HCQ
Retrospective Elevated ALT (1)
us
Chen et al [236] RA/Taiwan TOZ 8/RA (5),LEF (4), 12 months
Cohort study Stable viral loads (8)
CsA (1)
Mori et al [237] RA/Japan One case report TOZ TNFi failure None 8 months Elevated viral loads
an
Mahajan et al [238] RA/USA Two cases report ABT TNFi failure None 14,36 months Stable ALT & viral loads
MTX (8),
M
Retrospective Stable ALT & viral loads
Chen et al [236] RA/Taiwan ABT 15/RA HCQ(10) 12 months
Cohort study Decreased viral loads
LEF(4), CsA(3)
TNFi/TOZ Elevated viral loads (2),
d
Abdulaziz et al [239] RA/Saudi Arabia Two cases report ABT CS, csDMARDs 4, 11 months
failure elevated ALT (1)
Abdulaziz et al [239] RA/Saudi Arabia Case series te RTX
6/RA
TNFi failure
CS, csDMARDs 8-84 months
Elevated viral loads(2),
elevated ALT (1)
ep
Retrospective 6/RA HCQ(4) 25.8±16.7 Elevated viral loads
Chen et al [225] RA/Taiwan RTX
Cohort study TNFi failure SSZ (1) months compared to baseline
c
csDMARDs: conventional synthetic disease-modifying anti-rheumatic drugs; bDMARD, biologic disease-modified anti-rheumatic drug; AD:
Ac
autoimmune diseases; RA: rheumatoid arthritis; PsA: psoriatic arthritis; F-U: follow-up; NSAIDs: non-steroidal anti-inflammatory drugs; CS:
corticosteroids; MTX: methotrexate; CsA: cyclosporine A; HCQ: hydroxychloroquine; SSZ: sulfasalazine; LEF: lefluomide; TNFi: tumor
necrosis factor inhibitors; ETN: etanercept; IFX: infliximab; ADA: adalimumab; GOL: golimumab; TOZ: tocilizumab; ABT: abatacept; RTX:
61

62
rituximab; ALT: alanine aminotransferase; NA: not available.
t
rip
c
us
an
M
d
te
c ep
Ac
62

63
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ip
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Expert Review of Clinical Immunology

ISSN: 1744-666X (Print) 1744-8409 (Online) Journal homepage: https://www.tandfonline.com/loi/ierm20

Infection risk in patients undergoing treatment

Ying-Ming Chiu & Der-Yuan Chen

To link to this article: https://doi.org/10.1080/1744666X.2019.1705785

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Journal: Expert Review of Clinical Immunology

Infection risk in patients undergoing treatment for inflammatory arthritis:

Ying-Ming Chu1,2, Der-Yuan Chen1,2,3,4,5*

Medical University Hospital, Taichung, Taiwan

Translational Medicine, National Chung Hsing University, Taichung, Taiwan

University, Taichung, Taiwan

*Correspondence: Der-Yuan Chen, MD, PhD, Rheumatology and Immunology Center,

886-4-22052121, extension 4628; fax: 886-4-22073812; e-mail:

Information Classification: General

Information Classification: General

ABT: abatacept; ADA: adalimumab; AS: ankylosing spondylitis; bDMARDs:

biologic disease modifying anti-rheumatic drugs; CKD: chronic kidney disease;

COPD: chronic obstructive pulmonary disease; CS: corticosteroids; CsA:

cyclosporine A; csDMARDs: conventional synthetic disease modifying

HBsAg-positive; HBsAg-/anti-HBc+: HBsAg-negative anti-HBc antibodies-positive;

HCV: hepatitis C virus; HCQ: hydroxychloroquine: IFX: infliximab; IL-6:

interleukin-6; JAK: Janus kinase; LEF: leflunomide; LTBI: latent tuberculosis

psoriatic arthritis; PMS: post-marketing surveillance; RA: rheumatoid arthritis; TNF:

RTX: rituximab; 3HP: 3-month once-weekly isoniazid plus rifapentine; TB:

tuberculosis; tsDMARDs: targeted synthetic disease modifying anti-rheumatic drugs;

UTK: ustekinumab; WHO: World Health Organization

Information Classification: General

Introduction: Despite the therapeutic effectiveness of biologics targeting immune

cells or cytokines in patients with inflammatory arthritis, which reflects their

pathogenic roles, an increased infection risk is observed in those undergoing

Mycobacterium tuberculosis, and hepatitis virus in inflammatory arthritis patients

undergoing treatment with csDMARDs, bDMARDs, or tsDMARDs.

those receiving bDMARDs therapy, particularly TNF inhibitors. Regarding HBV

infection, antiviral therapy may effectively prevent HBV reactivation in patients

receiving bDMARDs, especially rituximab. However, more data are needed to

establish effective preventive strategies for HBsAg-negative/HBcAb-positive patients.

Information Classification: General

Keywords: Infection risk, treatment, non-biologics, biologics, inflammatory arthritis

Information Classification: General

1. Both csDMARDs and bDMARDs increase the risk of bacterial infection,

hepatologists is suggested in using DAAs according to the risk stratification.

5. The implementation of preventive strategies is needed to reduce the infection risks

in inflammatory arthritis patients undergoing therapies with bDMARDs or

Information Classification: General

Inflammatory arthritis is a chronic inflammatory disease marked by persisted

with RA [11]. To inhibit peripheral arthritis in ankylosing spondylitis (AS) and

biologics such as TNF inhibitors [12-14].

mortality [15-18], which may be due to disease-related immune dysfunction [19,20]

or the immunosuppressive effects of therapeutic agents [21,22]. Given that

pro-inflammatory cytokines are essential for human defense, the inhibitors to

cytokines or JAK may increase the risk of infections or reactivation of latent

Information Classification: General

tuberculosis infection (LTBI) or hepatitis virus infection [21-25]. Although

accumulating reports have indicated an increased risk of infections in adult patients

particularly in HBV endemic area [30-31]. In contrast to hepatitis B virus (HBV)

reactivation, hepatitis C virus (HCV) reactivation is relatively uncommon in patients

or oral JAK inhibitors [33,34].

Consequently, we aimed to review the impacts of treatment with non-biologics,