ORIGINAL ARTICLE
The Risk of Infections Associated With JAK Inhibitors in
Rheumatoid Arthritis
A Systematic Review and Network Meta-analysis
Carlos Alves, PhD,* Ana Penedones, PhD,† Diogo Mendes, PhD,† and Francisco Batel Marques, PhD*
Background/Objective: The Janus kinases (JAKs) are cytoplasmic ty-
rosine kinases associated with membrane cytokine receptors that mediate
signaling of multiple cytokines and growth factors, contributing to the
pathogenesis of multiple autoimmune disorders. The JAK inhibitors are a
new class of targeted therapies with proven efficacy in treating rheumatoid
arthritis but are associated with an increased risk of infections. This study is
aimed at comparing the relative safety of the different JAK inhibitors with
regard to the risk of serious infections in patients with rheumatoid arthritis.
Methods: PubMed, EMBASE, Cochrane Library, and clinicaltrials.gov
were searched to identify randomized controlled trials evaluating the effi-
cacy and safety of JAK inhibitors in patients with rheumatoid arthritis.
The outcomes assessed were the risk of total and serious infections, tuber-
culosis, and herpes zoster. Sensitivity analysis disaggregated the results ac-
cording to background therapy and licensed doses of JAK inhibitors.
Results: Thirty-seven randomized controlled trials that were included met
the inclusion criteria. Compared with filgotinib, adalimumab (4.81; 95%
confidence interval [CI], 1.39–16.66), etanercept (6.04; 95% CI, 1.79–20.37),
peficitinib (7.56; 95% CI, 1.63–35.12), tofacitinib (4.29; 95% CI, 1.43–12.88),
and upadacitinib (4.35; 95% CI, 1.46–13.00) have an increased risk of her-
pes zoster infection. Risk differences between the drugs became statisti-
cally nonsignificant when the sensitivity analysis was conducted.
Conclusions: The risk of infections seems to be similar among the cur-
rently approved JAK inhibitor drugs. Although the initial results suggested
that filgotinib could have a reduced risk of herpes zoster, the sensitivity
analyses did not support those findings.
Key Words: rheumatoid arthritis, JAK inhibitors, safety, infections, herpes
zoster, tuberculosis
(J Clin Rheumatol 2022;28: e407–e414)
R heumatoid arthritis is an autoimmune, chronic, and inflamma-
tory disease, which affects approximately 5 in every 1000 adults
worldwide.1 Several pharmacological options are available for the
management of this disease, namely, conventional synthetic (cs)
disease-modifying antirheumatic drugs (DMARDs), such as meth-
otrexate (MTX); targeted synthetic (ts) DMARDs, including the
Janus kinase (JAK) inhibitors; and biologic (b) DMARDs, such
as etanercept or infliximab.1,2 The use of JAK inhibitors is currently
From the *Faculty of Pharmacy, University of Coimbra; and †UFC–Coimbra
Regional Pharmacovigilance Unit, CHAD–Centre for Health Technology
Assessment and Drug Research, AIBILI–Association for Innovation and
Biomedical Research on Light and Image, Coimbra, Portugal.
The authors declare no conflict of interest.
Correspondence: Carlos Alves, PhD, Laboratory of Social Pharmacy and Public
Health, Faculty of Pharmacy, University of Coimbra, Polo Ciencias da
Saude, Azinhaga de Santa Comba, Celas 3000-548 Coimbra, Portugal.
E‐mail: carlosmiguel.costaalves@gmail.com.
Supplemental digital content is available for this article. Direct URL citation
appears in the printed text and is provided in the HTML and PDF versions
of this article on the journal’s Web site (www.jclinrheum.com).
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 1076-1608
DOI: 10.1097/RHU.0000000000001749
JCR: Journal of Clinical Rheumatology • Volume 28, Number 2, March 2022
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
foreseen in rheumatoid arthritis management guidelines.2 The
European League Against Rheumatism guidelines recommend
JAK inhibitors to treat patients with poor prognostic factors
who failed initial treatment with csDMARDs.2
In 2012, tofacitinib was the first JAK inhibitor approved by
the Food and Drug Administration for the treatment of rheumatoid
arthritis.3 Safety concerns, including the risk of serious infections,
delayed the approval of tofacitinib by the European Medicines
Agency (EMA) until 2017.3 In the same year, EMA also approved
baricitinib.3 However, the Food and Drug Administration rejected the
initial application for baricitinib because the overall benefit-risk
assessment was not favorable.4 After a reevaluation, the regula-
tory authority approved baricitinib 2 mg, but not the 4-mg dose,
because of safety reasons, including the potential thrombotic
risk.5 Upadacitinib and filgotinib were approved by the European
Union in 2019 and 2020, respectively.6,7 These drugs were placed
under additional safety monitoring by EMA.8 The other JAK inhib-
itors are still under clinical development, such as peficitinib.9,10
The JAK inhibitors have been associated with an increased
risk of serious infections, such as tuberculosis, herpes zoster reac-
tivation, pneumonia, gastritis, hepatitis, meningitis, aspergillosis,
or candidiasis.3,6,11,12 Such hazards are perceived to be a class ef-
fect, and it is recommended that all patients should be brought up
to date with all immunizations according to the current guidelines
before starting treatment with JAK inhibitors.6,11 However, each
JAK inhibitor is expected to selectively bind to specific JAK fam-
ily proteins within the cell.13 This may lead to differences in their
safety profiles, because each JAK member plays a given role in
the immune response.13 Therefore, it is important to compare the
risk of infections between the JAK inhibitors because these medi-
cines represent a pharmacological novelty.
This systematic review and network meta-analysis aimed to
compare the relative safety of the different JAK inhibitors with regard
to the risk of serious infections in patients with rheumatoid arthritis.
MATERIALS AND METHODS
This systematic review and network meta-analysis followed
the Centre for Reviews and Dissemination's guidance for undertak-
ing reviews in health care and was reported in accordance with the
PRISMA extension statement for reporting systematic reviews in-
corporating network meta-analyses of health care interventions
(Supplemental Table 1, http://links.lww.com/RHU/A291).14,15 This
systematic review was registered at PROSPERO (CRD42020190440)
and at European Network of Centres for Pharmacoepidemiology
and Pharmacovigilance (EUPAS35531), and a protocol was pre-
pared and published in the literature.16
Eligibility Criteria
Studies were considered for inclusion if they fulfill the fol-
lowing criteria:
• Study design: Phase 2 and phase 3 randomized controlled
trials (RCTs);
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Alves et al JCR: Journal of Clinical Rheumatology • Volume 28, Number 2, March 2022
• Population: Studies evaluating patients diagnosed with rheuma-
toid arthritis based on the American College of Rheumatology/
European League Against Rheumatism criteria17;
• Intervention: Only studies assessing the effects of JAK in-
hibitors (baricitinib, filgotinib, peficitinib, tofacitinib, and
upadacitinib) in the treatment of patients with rheumatoid ar-
thritis were included;
• Comparators: Studies comparing the intervention against
placebo, active treatment (DMARD), or no treatment;
• Outcomes: Any infection, serious infections (defined as
events leading to death, hospitalization, or need for antibi-
otic therapy),3 herpes zoster infection, and tuberculosis;
• Timing: No restrictions were applied to the length of follow-
up; and
• Language: Only studies reported in English were included.
Information Sources
PubMed, EMBASE, Cochrane Central Register of Controlled
Trials, and ClinicalTrials.gov were searched from their inception
until August 13, 2020. Bibliographic reference lists, systematic re-
views, and meta-analyses of all relevant studies were hand searched
to identify additional eligible studies.
Search Strategy
Search terms comprised rheumatoid arthritis and drug names,
including the thesaurus terms (MeSH and Emtree terms) and the in-
ternational nonproprietary names. No language filters will be ap-
plied. The search was updated at the end of the systematic review.
The search strategy is described in detail in Supplemental Table 2,
http://links.lww.com/RHU/A292.
Study Records
Two researchers independently screened the titles and ab-
stracts by hand and selected full articles for inclusion in accor-
dance with the prespecified eligibility criteria. Disagreements
were resolved by discussion and consensus with a third researcher.
Data Items
The following data were extracted from each study: reference,
year of publication, RCT phase (2 or 3), sample sizes, follow-up
length, intervention (name, dosage, frequency, and duration of
treatment), comparators, and data on the safety outcomes (total in-
fections, serious infections, herpes zoster infections, and tuberculo-
sis). Data were extracted from each included study by 2 researchers
independently to a predeveloped form.
Risk of Bias of the Individual Studies
The RoB 2 tool, a revised Cochrane risk of bias tool for ran-
domized trials, was used to assess the risk of bias of the individual
studies.18 The value of trial data on adverse effects relies on 2 ma-
jor characteristics: the rigor of monitoring for the adverse effects
during the study, in particular the infections, and the completeness
of reporting.
Data Synthesis
Odds ratios and their 95% confidence intervals (CIs) were
pooled. The risk estimates were considered statistically significant
if the 95% CIs do not contain the value 1. For studies evaluating
different doses of the same intervention, the number of events
and the number of exposures were added. When no events are
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reported in 1 or both groups, a continuity correction of 0.5 was
added to each cell.
A network map linking all the pharmacological treatments
was formed.19 The nodes of the network map show the pharmaco-
logic treatments being compared, and the edges show the available
direct comparisons between the treatments.
A sensitivity analysis was conducted to reassess the risks in-
cluding only data from (a) licensed doses of JAK inhibitors, and
(b) clinical trials using csDMARDs as antirheumatic background
therapy.
The inconsistency test was conducted to assess the extent of
disagreement between the direct and indirect evidence. Inconsis-
tency will be evaluated according to 3 approaches. The first ap-
proach tested the overall inconsistency, via Wald test.19 In the
second approach, each closed loop in the network was examined
(node splitting) to assess the local inconsistency between the risk
estimates from direct and indirect evidence.20 The “loop-specific”
approach (third) was performed to evaluate the inconsistency sep-
arately in every closed loop of the networks.20 For each network,
an inconsistency plot (ifplot) was produced where the inconsis-
tency factor and its 95% CI were estimated for each loop.
A comparison-adjusted funnel plot was used to test small-study
effect and publication bias.20
For each outcome, treatments were ranked according to the
probability of being the safest (best) alternative using the surface
under the cumulative ranking curve (SUCRA), expressed as a per-
centage.20 A higher SUCRAvalue is regarded as a better result for
an individual intervention. When ranking the treatments, the
closer the SUCRAvalue is to 100%, the higher the treatment rank-
ing. A SUCRAvalue of 0% suggests that the treatment is certainly
the worst.20 The league tables arrange the presentation of the sum-
mary estimates by ranking the treatments in the order of the most
pronounced impact on the outcome under consideration, accord-
ing to the SUCRAvalue.21 All the statistics were performed using
STATA 13.1 (StataCorp LP, College Station, TX).
RESULTS
Supplemental Figure 1, http://links.lww.com/RHU/A295
presents the flow of the search strategy criteria. The electronic
databases search returned 5131 references. After excluding du-
plicates and other studies with inadequate design, 37 studies
met the inclusion criteria (Supplemental references w1–w37,
http://links.lww.com/RHU/A304). The main characteristics of
the studies (design and follow-up duration, participants’ demo-
graphic characteristics, drugs under evaluation, and sample) are pre-
sented in Supplemental Table 3, http://links.lww.com/RHU/A293.
Most of the studies included patients on background therapy
with csDMARDs (n = 25) and compared JAK inhibitors with
placebo (n = 30).
The assessment of the risk of bias of the included studies is pre-
sented in Supplemental Figure 2, http://links.lww.com/RHU/A292.
Only 4 RCTs were judged as having a low risk of bias (w1, w19,
w24, w36). Lack of information on adverse event monitoring was
the main methodological impairment found among the studies.
Some studies did not provide detail on the allocation concealment
and/or randomization process.
Network Maps
Network maps are illustrated in Supplemental Figures 3A to 3D,
http://links.lww.com/RHU/A297. The size of the nodes indicates
the number of studies included in the corresponding nodes. The
thickness of the lines connecting 2 nodes indicates the amount of data
available for that comparison.
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JCR: Journal of Clinical Rheumatology • Volume 28, Number 2, March 2022 JAK Inhibitors and Infections: Meta-analysis

Total Infections http://links.lww.com/RHU/A298). The SUCRA ranking suggests

No differences were observed between the JAK inhibitors re-
garding the risk of total infections (Fig. 1; Supplemental Table 4A,
http://links.lww.com/RHU/A298). Compared with placebo,
tofacitinib (1.52; 95% CI, 1.16–1.98), upadacitinib (1.43; 95% CI,
1.18–1.73), adalimumab (1.29; 95% CI, 1.02–1.65), and MTX
(1.43; 95% CI, 1.17–1.73) increase the risk of total infections.
The ranking probability based on the SUCRA suggests that placebo
is probably the safest treatment (SUCRA = 0.883), followed by
peficitinib (SUCRA = 0.739) and baricitinib (SUCRA = 0.612)
(SUCRAs for the remaining drugs; filgotinib = 0.564; adalimumab
= 0.533; MTX = 0.354; upadacitinib = 0.346; tofacitinib = 0.252;
Pf-06650833 = 0.216) (Supplemental Fig. 4A, http://links.lww.com/
RHU/A298).
Serious Infections
No differences were observed between the treatments regard-
ing the risk of serious infections (Fig. 2; Supplemental Table 4B,
that peficitinib is probably the safest treatment (SUCRA = 0.815),
followed by placebo (SUCRA = 0.646) and Pf-06650833 (SUCRA =
0.635) (SUCRAs for the remaining drugs; etanercept = 0.616;
adalimumab = 0.609; tofacitinib = 0.505; baricitinib = 0.487;
filgotinib = 0.285; upadacitinib = 0.215; MTX = 0.189) (Supplemental
Fig. 4B, http://links.lww.com/RHU/A298).
Tuberculosis
No differences were observed between the treatments regarding
the risk of tuberculosis (Fig. 3; Supplemental Table 4C, http://links.
lww.com/RHU/A298). According to SUCRA ranking, baricitinib is
probably the safest treatment (SUCRA = 0.807), followed by MTX
(SUCRA = 0.561) and upadacitinib (SUCRA = 0.495) (SUCRAs
for the remaining drugs; filgotinib = 0.456; tofacitinib = 0.418;
placebo = 0.413; adalimumab = 0.350) (Supplemental Fig. 4C, http://
links.lww.com/RHU/A298).

FIGURE 1. Risk of total infections between treatments. Plac indicates placebo; Bari, baricitinib; Ada, adalimumab; Upa, upadacitinib; Mtx,
methotrexate; Tofa, tofacitinib; Pf, Pf-06650833; Filgo, filgotinib; Pef, peficitinib, PrI, prediction interval (95%).

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Alves et al JCR: Journal of Clinical Rheumatology • Volume 28, Number 2, March 2022

FIGURE 2. Risk of serious infections between treatments. Plac indicates placebo; Bari, baricitinib; Ada, adalimumab; Upa, upadacitinib; Mtx,
methotrexate; Tofa, tofacitinib; Pf, Pf-06650833; Filgo, filgotinib; Etan, etanercept; Pef, peficitinib; PrI, prediction interval (95%).

Herpes Zoster
Compared with filgotinib, adalimumab (4.81; 95% CI,
1.39–16.66), etanercept (6.04; 95% CI, 1.79–20.37), peficitinib
(7.56; 95% CI, 1.63–35.12), tofacitinib (4.29; 95% CI, 1.43–12.88),
and upadacitinib (4.35; 95% CI, 1.46–13.00) have an increased
risk of herpes zoster infection (Fig. 4; Supplemental Table 4D,
http://links.lww.com/RHU/A298). SUCRA ranking suggests that
filgotinib is probably the safest treatment (SUCRA = 0.968),
followed by placebo (SUCRA = 0.726) and baricitinib (SUCRA =
0.619) (SUCRAs for the remaining drugs; tofacitinib = 0.462;
upadacitinib = 0.445; MTX = 0.428; adalimumab = 0.399;
etanercept = 0.271; peficitinib = 0.182) (Supplemental Fig. 4D,
http://links.lww.com/RHU/A298).
Small-Study Effects and Publication Bias
Funnel plots provide an indication for the presence of
small-study effects for serious infections, herpes zoster, and tuber-
culosis network meta-analyses (Supplemental Figs. 5A–D, http://
links.lww.com/RHU/A299). In the case of herpes zoster, the plot in-
dicates that small studies tend to show that the active treatments are
less safe than their respective comparison-specific weighted aver-
age effect. The total infections’ plot denotes a slight asymmetry,
with a few more studies showing that active treatments are less safe.
There is no evidence of publication bias.
Inconsistency
The Wald test gave no evidence of inconsistency (p value for:
total infections = 0.487; serious infections = 0.914; herpes zos-
ter = 0.811; tuberculosis = 0.912). The node splitting, used for
the local test on loop inconsistency, did not identify significant
differences, except in 2 nodes in the network for total infections
(Supplementary Figs. 6A–D, http://links.lww.com/RHU/A300).
Supplemental Figures 7A, http://links.lww.com/RHU/A301
to D illustrates the inconsistency in the loops of the 4 networks, as-
suming a common loop-specific heterogeneity variance estimated
using the method of moments. The plots show that statistically

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JCR: Journal of Clinical Rheumatology • Volume 28, Number 2, March 2022 JAK Inhibitors and Infections: Meta-analysis

FIGURE 3. Risk of tuberculosis between treatments. Plac indicates placebo; Bari, baricitinib; Ada, adalimumab; Upa, upadacitinib; Mtx,
methotrexate; Tofa, tofacitinib; Filgo, filgotinib; PrI, prediction interval (95%).

significant inconsistency was not found for any of the loops, as all
95% CIs for RoRs are compatible with zero inconsistency (RoR =
1). However, some loops include values of high inconsistency
(RoR > 2), particularly among the networks for tuberculosis and
herpes zoster.
Sensitivity Analysis
After restricting the results to the licensed doses of JAK inhibitors,
the risk estimates for total infections, serious infections, and tuberculo-
sis did not significantly change from the initial analysis (Supplemental
Figs. 8A–C, http://links.lww.com/RHU/A302). Regarding herpes zos-
ter, increased risks were identified for the following comparisons:
etanercept versus placebo (2.85; 95% CI, 1.15–7.08), tofacitinib versus
filgotinib (3.32; 95% CI, 1.04–10.56), etanercept versus filgotinib
(5.02; 95% CI, 1.39–18.10), and adalimumab versus filgotinib (3.73;
95% CI, 1.02–13.57) (Supplemental Fig. 8D, http://links.lww.com/
RHU/A302).
When the results were reanalyzed by including only data from
studies evaluating JAK inhibitors associated with csDMARDs, in-
creased risks of total infections were identified when the following
drugs were compared with placebo: adalimumab (1.27; 95% CI,
1.05–1.53), MTX (1.40; 95% CI, 1.20–1.65), Pf-06650833 (1.63;
95% CI, 1.06–2.50), baricitinib (1.97; 95% CI, 1.31–2.97), and
upadacitinib (1.57; 95% CI, 1.34–1.84) (Supplemental Fig. 8A,
http://links.lww.com/RHU/A302). No differences between the
treatments were observed for serious infections, tuberculosis,
and herpes zoster outcomes (Supplemental Figs. 9B–D, http://
links.lww.com/RHU/A303).
DISCUSSION
Patients with rheumatoid arthritis have higher susceptibility
to develop infections.22,23 Such vulnerability can be explained
by the pathophysiology of the disease, associated complications,
or as a consequence of the immunosuppressive treatments.22
Therapeutic options for rheumatoid arthritis are currently vast,
but no significant differences in the efficacy profile are noted be-
tween treatments, particularly among second-line alternatives
(bDMARDs and tsDMARDs).24 For this reason, safety poses as
a major aspect in the clinical decision-making process, where
the risk of infection should be accounted for. The bDMARDs
are associated with an increased risk of serious infections in rheu-
matoid arthritis, such as tuberculosis, hepatitis B and C, herpes

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Alves et al JCR: Journal of Clinical Rheumatology • Volume 28, Number 2, March 2022

FIGURE 4. Risk of herpes zoster between treatments. Plac indicates placebo; Bari, baricitinib; Ada, adalimumab; Upa, upadacitinib; Mtx,
methotrexate; Tofa, tofacitinib; Filgo, filgotinib; Etan, etanercept; Pef, peficitinib, PrI, prediction interval (95%).

zoster reactivation, pneumonia, meningitis, necrotizing fasciitis,
septic arthritis, coccidioidomycosis, or histoplasmosis.25–28 Al-
though no differences in the risk of infections have been identified
across the bDMARDs, it is relevant to understand if the same
could be expected among the tsDMARDs.24 The results of this
systematic review and network meta-analysis suggest filgotinib
has a reduced risk of herpes zoster when compared with other
JAK inhibitors, namely, peficitinib, tofacitinib, and upadacitinib.
No risk differences were identified among the drugs of this class
for the remaining outcomes.
Herpes zoster, resulting from reactivation of varicella zoster
virus, is perhaps the most characteristic infection from JAK inhibi-
tors and may be considered a “class effect.”13 An observational
study found that tofacitinib was associated with an increased risk
of serious infections leading to hospitalization when compared with
etanercept.29 Moreover, patients treated with tofacitinib had a 2-fold
higher risk of herpes zoster compared with bDMARDs initiators.
An RCTwith 48 weeks of follow-up found that the event rate of her-
pes zoster was higher on patients treated with upadacitinib than
with adalimumab.30 The pharmacological interest in this new drug
class arose from the immunosuppression in humans resulting from
defects in JAKs, which, in turn, explains the occurrence of infec-
tions.13 Janus kinase inhibitors are small molecules targeting the
JAK family (JAK1, JAK2, JAK3, and tyrosine kinase 2) at an intra-
cellular level.31,32 These kinases are bound to cytokine receptors
(type I and II) and transmit subsequent signals that activate addi-
tional signal transducers and activators of transcription (STATs),
driving proinflammatory mechanisms of the cellular immune re-
sponse, such as lymphocyte proliferation and homeostasis, erythro-
poiesis, myelopoiesis, and antiviral and antitumoral response.13 The
JAK/STAT signaling plays a central role in the development and
maturation of natural killer cells, which are essential in the immune
response to herpes zoster.33 Together with JAK1, JAK3 transmits
signals from several cytokines resulting in the phosphorylation of
several STATs. However, although JAK3 expression is restricted
to the lymphoid lineage, JAK1 is expressed in many cells and tis-
sues.34 The several JAK inhibitors have different potency of enzy-
matic inhibition. Filgotinib is highly selective for JAK1 over the
other JAKs comparing to the other inhibitors.35 It is suggested that
avoiding JAK3 inhibition may lead to less immunosuppression,
which, in some way, helps in explaining the risk differences in
herpes zoster between filgotinib and other JAK inhibitors.34,36

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JCR: Journal of Clinical Rheumatology • Volume 28, Number 2, March 2022
However, although there is a pharmacological rationale provid-
ing some support to the observed risk differences, the sensitivity
analyses conducted did not return the same results as the initial
analysis, suggesting caution before drawing conclusions.
The selective targeting of the JAKs seems to be dose depen-
dent, as higher doses of JAK inhibitors may block other members
of the JAK family.3 Because the immune system response is me-
diated by the JAK-STAT pathway, a dose-dependent change in
the risk of infections may develop. Therefore, it is relevant to assess
the safety profile of JAK inhibitors by restricting the data included in
the analysis to those from the licensed doses. When such sensitivity
analysis was conducted, the only statistically significant increased
risk of herpes zoster found was from tofacitinib when compared
with filgotinib. For the remaining outcomes, risk estimates did not
significantly change when compared with the initial analysis. More-
over, when the analysis was restricted to studies evaluating JAK in-
hibitors associated with csDMARDs, no differences between the
treatments were observed for serious infections, tuberculosis, and
herpes zoster. These findings suggest that when these comparisons
are conducted under the regulatory approved conditions, that is, li-
censed doses and as add-on alternatives to csDMARDs, differ-
ences in the herpes zoster risk between the JAK inhibitors may
be restricted, at the limit, to the tofacitinib-filgotinib comparison.
Only 4 of the 37 studies were assessed as having “low risk of
bias.” Most of the studies did not provide information on the ad-
verse events monitoring process. Also, some studies did not provide
details on the allocation concealment and/or randomization process.
Resulting from the immunosuppression, infections are an expected,
potentially serious, adverse reaction from antirheumatic pharmaco-
therapy.22,23 Yet, just 4 studies elected infections as an adverse event
of special interest, for which ongoing monitoring and prompt
reporting by the investigator to the sponsor is appropriate (w1,
w19, w24, w36). Given the risk of bias assessment results, a sen-
sitivity analysis was not conducted on this subject since it would
add little to the interpretation of the findings of this meta-
analysis. It should be noted, however, that the protocols of most
of the clinical trials were not publically available, preventing car-
rying out a thorough assessment of their methodological quality.
A previous meta-analysis evaluated the risk of serious infec-
tions in rheumatoid arthritis patients treated with JAK inhibitors.3
The indirect comparisons did not identify a notable difference in
the risk of herpes zoster between the JAK inhibitors. At the time
the authors conducted the meta-analysis, evidence was only avail-
able for tofacitinib, baricitinib, and upadacitinib. Moreover, indi-
rect treatment comparisons were perform just for 2 outcomes,
serious infections and herpes zoster, because data on further op-
portunistic infections were too rare to allow additional analyses.
One of the strengths of the meta-analysis by Bechman and col-
leagues was the restriction of the evidence to licensed doses of
JAK inhibitors, an approach adopted in the sensitivity analysis
of the present meta-analysis.3 Even so, despite not having included
evidence for all JAK inhibitors, the results of both meta-analyses
tend to point that there are no significant risk differences for serious
infections and herpes zoster.
There are additional limitations that should be addressed.
First, between-studies heterogeneity is noted in the total infections
and tuberculosis meta-analyses, where the 95% prediction inter-
vals (PrIs) are wider than CIs. For serious infections and herpes
zoster meta-analyses, PrIs almost overlap the CIs. Although
JAK inhibitors may have been developed under similar clinical
programs, the studies included in this meta-analysis present demo-
graphic and methodological differences, namely, in the sample
sizes, clinical trial phase, follow-up duration, background therapy,
and geographic recruitment locations. Therefore, the results of this
network meta-analysis should be interpreted in the light of the
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Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
JAK Inhibitors and Infections: Meta-analysis
magnitude of heterogeneity. Second, the Wald test and the incon-
sistency factors from ifplots did not return statistically significant
results. However, in the networks of total infections, serious infec-
tions, and herpes zoster, all the existing evidences for a few con-
trasts come from trials directly comparing the correspondent
treatments. Moreover, RoRs > 2 were identified for some loops,
which means that the direct estimate can be twice as large as the
indirect estimate or the opposite (the indirect estimate is twice
the direct). Thus, safe conclusions on the absence of inconsistency
cannot be drawn. Third, the frequency of certain types of opportu-
nistic serious infections reported in the RCTs was rare or even
nonexistent, preventing to compare the relative risk of additional
outcomes, such as Pneumocystis jirovecii pneumonia (PJP),
oro-esophageal candidiasis, hepatitis C, encephalitis, or infections
caused by West Nile, John Cunningham, Zika, or Chikungunya
virus. The low rate of those events even prevented the inclusion
of peficitinib in the network meta-analysis, which evaluated the
risk of tuberculosis. Nevertheless, such limitation was expected,
given that most of the studies included have small sample sizes
and short follow-up durations, reducing the chances of identifying
rare adverse events. The detection of small-study effects for serious
infections, herpes zoster, and tuberculosis network meta-analyses
reinforces this conclusion. Fourth, although patients included in
the all RCTs were allowed to continue treatment with nonsteroidal
anti-inflammatory drugs and corticosteroids at stable doses, the
safety results were not disaggregated based on usage of such med-
icines. Moreover, some RCTs did not report the proportion of pa-
tients using corticosteroids, precluding further sensitivity analyses.
Therefore, there is a possibility that such drugs have introduced
confounding in the results. Corticosteroids increase the risk of se-
rious infections when continuously used, including certain oppor-
tunistic infections (eg, herpes zoster, tuberculosis, and PJP).37
Although corticosteroids have a place in the therapeutic arsenal,
clinical guidelines recommend their use at the lowest dose possible
and for the shortest time.38 Fifth, 37 clinical trials met the inclusion
criteria in this network meta-analysis, but only 3 evaluated filgotinib.
Most of the studies are from tofacitinib, baricitinib, and upadacitinib.
The publication in the scientific literature of further evidence from
ongoing clinical trials may produce changes in the results of the
current meta-analysis. Sixth, this network meta-analysis was not de-
signed to compare JAK inhibitors with other antirheumatic drugs
(adalimumab, etanercept, MTX). The literature was reviewed to
identify only RCTs evaluating JAK inhibitors in rheumatoid arthri-
tis, and the networks established in this meta-analysis do not include
RCTs of additional antirheumatic drugs. For this reason, the risk dif-
ferences between JAK inhibitors and adalimumab, etanercept, and
MTX presented in this study lack of statistical robustness. Seventh,
no study from decernotinib was included in this systematic review,
which constitutes a deviation from the protocol. However, this was
because of the fact that the clinical development of decernotinib in
rheumatoid arthritis has been discontinued, reducing the clinical
significance of establishing comparisons with this drug.39
In light of the current available evidence, JAK inhibitors
seem to present a similar risk of infections in the treatment of pa-
tients with rheumatoid arthritis. Although the results may have sug-
gested that filgotinib was associated with a reduced risk of herpes
zoster, the sensitivity analyses and the limitations of this work did
not support the initial findings. Postmarketing pharmacovigilance
evidence will be of utmost importance in the assessment of the
comparative risk of serious infections between the JAK inhibitors.
KEY POINTS
• There is a need to clarify the relative risk of infections among
the JAK inhibitors to support clinical decision making.
www.jclinrheum.com e413
Alves et al JCR: Journal of Clinical Rheumatology • Volume 28, Number 2, March 2022
• Initial analyses found a reduced risk of herpes zoster for filgotinib,
but these findings were not confirmed by the sensitivity analyses.
• JAK inhibitors’ risk of infections seems similar, but it needs
confirmation from postmarketing pharmacovigilance evidence.
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