Rheumatol Ther (2023) 10:387–404
https://doi.org/10.1007/s40744-022-00525-x
ORIGINAL RESEARCH
Serious Infection Rates Among Patients with Select
Autoimmune Conditions: A Claims-Based
Retrospective Cohort Study from Taiwan and the USA
Wen-Nan Huang . Ching-Yi Chuo . Ching-Heng Lin .
Yi-Ming Chen . Wei-Szu Lin . Katie Tuckwell . Nicholas S. Jones .
Joshua Galanter . Lisa Lindsay
Received: October 5, 2022 / Accepted: December 13, 2022 / Published online: December 26, 2022
Ó The Author(s) 2022
ABSTRACT
Introduction: Serious infections are an impor-
tant concern for patients with autoimmune
conditions. We sought to estimate serious
infection rates among patients with select
autoimmune conditions relative to the general
population in Taiwan and the USA.
Supplementary Information The online version
contains supplementary material available at https://
doi.org/10.1007/s40744-022-00525-x.
W.-N. Huang
Y.-M. Chen
Division of Allergy, Immunology, and
Rheumatology, Department of Internal Medicine,
Taichung Veterans General Hospital, Taichung,
Taiwan
W.-N. Huang
Y.-M. Chen
School of Medicine, National Yang Ming Chiao
Tung University, Taipei, Taiwan
W.-N. Huang
Department of Business Administration, Ling-Tung
University, Taichung, Taiwan
W.-N. Huang
Y.-M. Chen
College of Medicine National Chung Hsing
University, Taichung, Taiwan
C.-Y. Chuo
L. Lindsay (&)
RWD Enabling Platform, Product Development Data
Science, Genentech Inc, South San Francisco, CA,
USA
e-mail: lindsal1@gene.com
Methods: This retrospective cohort study esti-
mated setting-specific standardized serious
infection incidence rates and ratios among
patients with systemic lupus erythematosus,
including extra-renal lupus and lupus nephritis,
rheumatoid arthritis and primary membranous
nephropathy, compared with the general pop-
ulation using insurance claims for hospitaliza-
tions between 2000 and 2013. Multivariable
Cox proportional hazard models were used to
estimate adjusted hazard ratios for serious
infections, adjusting for age, sex, index year,
prior serious infection, comorbidities and
C.-H. Lin
Y.-M. Chen
W.-S. Lin
Department of Medical Research, Taichung Veterans
General Hospital, Taichung, Taiwan
C.-H. Lin
Department of Public Health, College of Medicine,
Fu Jen Catholic University, New Taipei City, Taiwan
C.-H. Lin
Institute of Public Health and Community Medicine
Research Center, National Yang Ming Chiao Tung
University, Taipei, Taiwan
C.-H. Lin
Department of Industrial Engineering and
Enterprise Information, Tunghai University,
Taichung, Taiwan
C.-H. Lin
Department of Health Care Management, National
Taipei University of Nursing and Health Sciences,
Taipei, Taiwan
388
medications.
Results: In Taiwan, serious infection rates were
22.7, 28.7, 70.6, 43.4 and 215.3 per 1000 per-
son-years among the general population and
among cohorts of patients with primary mem-
branous nephropathy, rheumatoid arthritis,
extra-renal lupus and lupus nephritis, respec-
tively. In the USA, serious infection rates were
2.6, 9.0, 15.6, 21.0 and 63.3 per 1000 person-
years among the general population and among
cohorts of patients with primary membranous
nephropathy, rheumatoid arthritis, extra-renal
lupus and lupus nephritis, respectively. Patients
had significantly higher serious infection rates
than the general population in both settings,
largely driven by bacterial, respiratory, urinary
tract and opportunistic infections. Patients with
lupus nephritis had the highest burden of seri-
ous infections relative to the general popula-
tion, with 7- to 25-fold higher adjusted hazard
ratios in Taiwan and the USA, respectively.
Conclusion: This study identified a significant
excess serious infection burden among patients
with targeted autoimmune conditions com-
pared with the general populations in Taiwan
and the USA.
Keywords: Serious infection; Incidence; Lupus;
Rheumatoid arthritis; Primary membranous
nephropathy; Autoimmune
Key Summary Points
Why carry out this study?
Understanding serious infection rates
among patients with autoimmune
conditions who are receiving standard-of-
care therapy in different settings is
important for the development and
introduction of new immune-targeted
therapeutics, as well as for decisions
related to disease management.
K. Tuckwell
N. S. Jones
J. Galanter
Early Clinical Development, Genentech Inc, South
San Francisco, CA, USA
J. Galanter
Product Development Safety, Genentech Inc, South
San Francisco, CA, USA
Rheumatol Ther (2023) 10:387–404
This study aimed to estimate serious
infection rates among patients with select
autoimmune conditions relative to the
general population in settings from 2
different regions that had similar data
sources and disease classification methods
What was learned from this study?
Serious infection rates are significantly
higher among autoimmune patients
relative to the general population both in
Taiwan and the USA.
Among the targeted autoimmune
conditions, patients with lupus nephritis
have particularly high rates of serious
infections.
These findings provide evidence that can
facilitate treatment decisions for patients
and aid in the development and
introduction of new immune-targeted
therapeutics
INTRODUCTION
Serious infections are an important concern for
patients with autoimmune conditions. This is
because of the effects of alterations in immune
function due to the disease itself, which can
lead to impaired cellular and humoral immune
function, as well as the effect of immunosup-
pressive therapies (e.g. high-dose steroids and
cyclophosphamide) used to control disease
activity [1–15]. Opportunistic infections, reac-
tivation of latent infections and more severe
manifestation of common infections are fre-
quently reported among patients with autoim-
mune conditions and are leading causes of
morbidity and mortality among patients with
conditions such as systemic lupus erythemato-
sus (SLE) or rheumatoid arthritis (RA), as well as
autoimmune conditions that lead to renal
manifestations such as lupus nephritis and pri-
mary membranous nephropathy [13, 16–27].
Furthermore, impaired renal function can lead
to immune dysfunction and may be an inde-
pendent risk factor for serious infections [28].
Rheumatol Ther (2023) 10:387–404
Understanding serious infection rates among
patients with autoimmune conditions who are
receiving standard-of-care therapy in different
settings is important for the development and
introduction of new immune-targeted thera-
peutics, as well as for decisions related to disease
management. Existing and novel B-cell deple-
tion or modulation therapies targeting CD20,
CD19, Bruton’s tyrosine kinase inhibitors and/
or B-cell activating factor are increasingly being
used in patients with autoimmune conditions
[29, 30]. Because global clinical trials are com-
mon for new therapeutic treatment efforts,
characterizing regional variability in serious
infection rates among patients with autoim-
mune conditions can provide valuable insights
into the influence of patient-level characteris-
tics, healthcare system(s) and treatment
approaches in routine clinical practice [31].
In this study, we identified a select group of
autoimmune conditions targeted by B-cell
depletion therapies to estimate the incidence of
serious infections, namely SLE, RA and primary
membranous nephropathy, compared with the
general population in both Taiwan and the
USA.
METHODS
Study Design and Source Populations
In this retrospective cohort study, we used data
from the National Health Insurance Research
Database (NHIRD) in Taiwan (the One Million
General Sample Database [OMGSD] and the
Catastrophic Illness Database [CID]) and the
U.S.-based Truven Healthcare MarketScanÒ
Commercial Claims (CC) and Encounters, as
well as the Supplemental Medicare databases
from 1 January 2000 to 30 December 2013. The
NHIRD includes medical insurance claims data
from an estimated 99.99% of Taiwan’s popula-
tion (approximately 23 million) as part of a
single-payer mandatory National Insurance
Program that includes patients’ records from
birth until death [32]. In Taiwan, patients
identified via the NHIRD OMGSD were ran-
domly sampled from the NHIRD in 2000 and
provided follow-up time through 2013. The CID
389
includes healthcare records for patients with a
catastrophic illness certification for select con-
ditions that entitles them to financial subsidies
to cover out-of-pocket medical costs. The U.S.-
based MarketScan CC database contains up to
109 million commercially insured individuals
aged \ 65 years who receive employer-spon-
sored health insurance and 8 million Medicare
commercially insured patients aged C 65 years,
annually. U.S. patients provided follow-up time
while enrolled in health insurance plans that
contributed to MarketScan CC and Medicare
between 2000 and 2013. Data from both Taiwan
and the USA included de-identified patient-
level demographic, medical and pharmacy data
collected and reported for the purpose of
insurance claims.
Study Population
The study population included person-time for
patients of all ages who had continuous
enrollment for C 90 days pre-index
and C 365 days post-index between 1 January
2000 and 31 December 2013. Patients were
excluded if they had cancer, solid-organ or bone
marrow transplant and/or HIV/AIDS (Electronic
Supplementary Material [ESM] Table S1).
We constructed mutually exclusive patient
cohorts to identify patients with SLE (extra-re-
nal lupus and lupus nephritis), RA and primary
membranous nephropathy, as well as to iden-
tify the general population within the NHIRD
OMGSD from Taiwan and the U.S.-based Mar-
ketScan CC and Medicare databases. The diag-
nostic algorithms used to identify patient
cohorts are described in the following sections.
Index dates were assigned for SLE (extra-renal
lupus and lupus nephritis separately), RA and
primary membranous nephropathy cohorts
based on the initial claim satisfying the speci-
fied criteria. The index date for the general
population was considered to be the first day
after 90 days of continuous enrollment within
the study period. We further characterized
patients from Taiwan with SLE and RA identi-
fied in the OMGSD according to their presence
in the CID during the same period.
390
SLE: Extra-Renal Lupus and Lupus Nephritis
Patients with SLE were identified if they had C 1
inpatient or C 2 outpatient claims with an
International Classification of Diseases, Ninth
Revision (ICD-9; https://apps.who.int/iris/
handle/10665/39473) diagnostic code of 710.0
separated by C 7 days and B 365 days. Patients
with SLE were further classified as having lupus
nephritis if they had C 1 inpatient or C 2 out-
patient claims with the ICD-9 diagnostic codes
580–586 and a lupus nephritis index date
within ± 365 days of the SLE index date.
Patients with extra-renal lupus were considered
those individuals who did not have evidence of
lupus nephritis within the 365-day post-index
period.
Rheumatoid Arthritis
Patients with RA were identified if they had C 1
inpatient or C 2 outpatient claims with ICD-9
diagnostic code of 714.0 separated by C 7 days
and B 365 days.
Primary Membranous Nephropathy
Patients with primary membranous nephropa-
thy were identified if they had C 1 inpatient
or C 2 outpatient claims with an ICD-9 diag-
nostic code of 581.1 or 582.1 separated
by C 7 days and B 365 days and did not have
any evidence of a secondary cause of membra-
nous nephropathy (ESM Table S2).
General Population
Individuals who satisfied the inclusion and
exclusion criteria and did not fulfill the criteria
for the SLE, RA or primary membranous
nephropathy cohorts were included in the
general population cohort.
Ethics Compliance
The protocol for this study is in line with the
2008 Declaration of Helsinki and its subsequent
amendments. The authors conducted secondary
research using de-identified U.S. data licensed
from IBMÒ WatsonÒ question-answering com-
puter system in compliance with U.S. Code of
Federal RegulationsTitle 45 (45 CFR) Sec-
tion 164.514(a–c) and the National Health
Rheumatol Ther (2023) 10:387–404
Insurance Program in Taiwan. The data from
both the USA and Taiwan had identifying
information removed and were coded in such a
way that the data could not be linked back to
subjects from whom it was originally collected.
This research does not require Institutional
Review Board or ethics review, as analyses with
these data do not meet the definition of ‘‘re-
search involving human subjects,’’ defined as
living individuals about whom an investigator
obtains identifiable private information for
research purposes. Furthermore, use of claims
data from Taiwan included in this research was
approved by the Taichung Veterans General
Hospital Institutional Review Board I and II
(CE13152B-8). Neither the provider of the data
nor the researchers were able to link the data
with identifiable individuals. Consent to par-
ticipate was not applicable in this retrospective
observational study of de-identified data.
Outcomes
Incident serious infections were identified based
on hospitalization that included an ICD-9
diagnostic code(s) pertaining to infections
occurring as the primary (most important)
diagnosis. Initial infections were identified that
occurred B 365 days post-index date for all
patient cohorts. We categorized serious infec-
tions as a composite set of infections, as well as
according to infection subtype [16] (ESM
Table S3).
Cofactors
The following cofactors were assessed for each
patient: age, sex, index year, pre-existing serious
infection, comorbid condition(s), and systemic
steroid (considered as those that were adminis-
tered orally, intravenously or intramuscularly)
and immunosuppressant use (ESM Table S4).
We captured patient age and sex based on data
contained in the enrollment files. Pre-existing
serious infections were considered as hospital-
izations due to serious infections identified
during the 90-day pre-index period. We classi-
fied patients according to the presence of con-
current autoimmune conditions (other than
Rheumatol Ther (2023) 10:387–404
SLE, RA and primary membranous nephropa-
thy) (ESM Table S5) and individual comorbid
conditions that contribute to the Charlson
Comorbidity Index (with the exception of those
targeted by the inclusion/exclusion study crite-
ria) identified via diagnostic claims at any time
during the study period (e.g. pre-index through
to 365 days post-index) [33]. We captured
claims for systemic corticosteroids and
immunosuppressants as a dichotomous (yes/
no) variable and the date when administered
and/or filled post-index until either the occur-
rence of a serious infection or 365 days post-
index.
Statistical Analyses
Incidence rates and ratios were calculated for
initial serious infections and 95% confidence
intervals (CIs) using both direct and indirect
standardization based on the general popula-
tion for Taiwan as well as the USA to provide
straightforward rate estimations and also
account for the influence of small numbers in
some strata [34, 35]. Standardization was based
on age, sex, index year, pre-existing serious
infection and systemic steroid and immuno-
suppressant use. Standardized incidence ratios
compared serious infection rates among
patients with a specified autoimmune condition
to the within-setting general population. Cox
proportional hazard models were used to esti-
mate serious infection hazard rates, adjusting
for index year, age, sex, prior serious infection,
co-existing comorbidities and post-index
receipt of corticosteroids or immunosuppres-
sant(s). For these models, we used 1–10 match-
ing for all cohorts on age, sex and index year to
account for potential differences in data struc-
ture between Taiwan and the USA.
Additional Analyses
In Taiwan, patients with major rheumatologic
conditions, such as SLE and RA, are provided
with a catastrophic illness certification that
entitles them to financial subsidies to cover out-
of-pocket medical costs. Patients with this cer-
tification have their healthcare records captured
391
in the CID. The CID has greater specificity than
the OMGSD due to rigorous review of patients’
diagnoses by rheumatologists commissioned by
the Bureau of National Health Insurance.
However, the CID is less generalizable to
patients identified via diagnostic algorithms
(e.g. as identified in the OMGSD for Taiwan and
in the U.S.-based claims data) because patients
with a catastrophic illness certificate may differ
with respect to disease severity or duration and/
or access to healthcare and medications. Fur-
thermore, there is no comparable system in the
USA. Thus, for patients from Taiwan only, we
used the CID to compare the characteristics and
serious infection rates of patients with SLE and
RA who were identified via diagnostic claims
algorithms in the OMGSD with those of
patients who were identified via diagnostic
claims and were also present in the CID.
RESULTS
Study Population
Figure 1 (Taiwan) and Fig. 2 (USA) provide the
study population attrition for the inclusion and
exclusion criteria for each cohort. The cohort-
specific population size for Taiwan was RA =
8606, lupus nephritis = 325, extra-renal
lupus = 1149, primary membranous nephropa-
thy = 127 and general population = 912,302.
The cohort-specific population size for the USA
was RA = 154,255, lupus nephritis = 3725,
extra-renal lupus = 41,904, primary membra-
nous nephropathy = 3377 and general
population = 640,412.
Table 1 shows the distribution of patient
characteristics for each cohort based on the
claims data from both settings. The general
population cohorts in Taiwan and the USA were
similar with respect to age (mean 33 years),
concurrent autoimmune conditions (approx.
3% had autoimmune conditions other than
extra-renal lupus, lupus nephritis, RA or pri-
mary membranous nephropathy) and medica-
tion use (systemic steroids and
immunosuppressants). Comorbidities, such as
cerebrovascular, chronic pulmonary and liver or
peptic ulcer disease, were more common among
392
Fig. 1 Patient cohorts in study population of Taiwan. AI
autoimmune, ERL extra-renal lupus, HIV/AIDS human
immunodeficiency virus/acquired immunodeficiency syn-
drome, ICD-9 International Classification of Diseases,
patients from Taiwan relative to those from the
USA. We identified modest differences between
post-index claims for systemic steroids and
immunosuppressants in Taiwan and the USA.
RA patients from Taiwan had fewer systemic
steroid and immunosuppressant claims than
U.S. patients, whereas patients with lupus
nephritis from Taiwan were more commonly
treated with cytostatic and antiproliferative
medications. Use of biologics was infrequent
except among U.S. patients with RA due to lack
of approval and reimbursement for target indi-
cations during the study period.
Serious Infections
Table 2 describes the standardized serious
infection rates and distribution of serious
infections by patient cohort for Taiwan and the
USA. Among the patient cohorts assessed,
patients with lupus nephritis experienced the
highest frequency of serious infections
Rheumatol Ther (2023) 10:387–404
Ninth Revision, ipt inpatient, LN lupus nephritis, NHIRD
National Health Insurance Research Database, opt outpa-
tient, pMN primary membranous nephropathy, RA
rheumatoid arthritis, SLE systemic lupus erythematosus
regardless of setting. Overall, serious infections
were largely driven by bacterial, respiratory,
urinary tract and opportunistic infections
among patient cohorts other than the general
population in both settings. In Taiwan, pedi-
atric patients with lupus nephritis, extra-renal
lupus and RA experienced a slightly higher
proportion of serious infections than their adult
counterparts, which was not observed in the
USA (ESM Fig. S1).
Among patients who had a serious infec-
tion B 365 days post-index, the average time to
the event was longer among patients from Tai-
wan with SLE, RA and primary membranous
nephropathy than among U.S. patients with the
same condition and longer in the general pop-
ulations of both settings compared with the
autoimmune cohorts (ESM Table S6).
Comparisons of serious infection rate to that
of the general population for each setting and
patient cohort are shown in Fig. 3. We identi-
fied the highest serious infection rates among
Rheumatol Ther (2023) 10:387–404
Fig. 2 Patient cohorts in study population of USA. Note
that the general population cohort in the USA is based on
a 1% random sample of IBMÒ MarketScanÒ Commercial
Claims and Encounters Database. CCAE IBMÒ
patients with lupus nephritis in both settings
and the lowest serious infection rates among
patients with RA. Due to low serious infection
rates in the U.S. general population, estimated
serious infection rates in the USA were elevated
for all patient cohorts.
Adjusted multivariable model results
accounting for age, gender, index year, medi-
cations and comorbidities identified signifi-
cantly heightened rates of serious infections
among patients with autoimmune conditions
relative to the general population in both Tai-
wan and the USA. Consistent with the descrip-
tive findings, the highest adjusted hazard ratios
(aHRs) were identified among patients with
lupus nephritis (Taiwan: aHR 7.4, 95% CI
4.5–12.4; USA: aHR 24.9, 95% CI 19.8–31.3),
followed by patients with primary membranous
nephropathy (Taiwan: aHR 3.3, 95% CI 1.4–7.8;
USA: aHR 10.4, 95% CI 8.1–13.4), extra-renal
lupus (Taiwan: aHR 2.4, 95% CI 1.4–4.0; USA:
aHR 6.3, 95% CI 5.5–7.2) and RA (Taiwan:
aHR 1.3, 95% CI 1.0–1.8; USA: aHR 5.5, 95% CI
393
MarketScanÒ Commercial Claims and Encounters Data-
base, MDCR MarketScan Medicare Supplemental and
Coordination of Benefits Database, MN membranous
nephropathy; for other abbreviations, see Fig. 1 caption
4.8–6.3). Assessment of the interactive effects of
autoimmune condition and medications con-
sistently identified heightened aHRs for serious
infection among patients who had a post-index
claim for systemic steroids compared to those
who did not within the same patient group (e.g.
Taiwan: extra-renal lupus, aHR 1.9, 95% CI
1.1–3.2; lupus nephritis, aHR 1.4, 95% CI
0.8–2.7; RA, aHR 1.3, 95% CI 1.0–1.6; primary
membranous nephropathy, aHR 2.3, 95% CI
0.8–6.5; USA: extra-renal lupus, aHR 1.4, 95%
CI 1.2–1.6; lupus nephritis, aHR 1.2, 95% CI
0.9–1.5; RA, aHR 1.1, 95% CI 0.9–1.2; primary
membranous nephropathy, aHR 1.6, 95% CI
1.1–2.3). The influence of immunosuppressants
on aHR of serious infection was mixed across
autoimmune cohorts and not consistent
between settings (e.g. Taiwan: extra-renal lupus,
aHR 1.0, 95% CI 0.4–2.3; lupus nephritis,
aHR 1.99, 95% CI 0.9–4.2; RA, aHR 1.1, 95% CI
0.6–2.1; primary membranous nephropathy,
aHR 0.7, 95% CI 0.2–2.1; USA: extra-renal
lupus, aHR 0.7, 95% CI 0.5–0.9; lupus nephritis,
Table 1 Characteristics of study populations in Taiwan and the USA
394

Patients, Variable Taiwana USAb

General SLE RA pMN General SLE RA pMN
population ERL LN populationc ERL LN
n 9,12,302 1149 325 8606 127 6,40,412 41,904 3725 1,54,255 3377
Age, mean (SD), years 32.7 (20.1) 36.2 37.8 51.4 51.0 32.7 (19.9) 45.9 43.4 53.8 (14.8) 43.7
(16.4) (20.1) (15.8) (19.8) (14.2) (17.2) (17.1)
Age \ 18 years, n (%) 235,591 (25.8) 137 61 163 (1.9) 8 (6.3) 176,720 (27.6) 1080 (2.6) 260 (7.0) 1978 (1.3) 317 (9.4)
(11.9) (18.8)
Age C 18 years, n (%) 676,711 (74.2) 1012 264 8443 119 463,692 (72.4) 40,824 3465 152,277 3060
(88.1) (81.2) (98.1) (93.7) (97.4) (93.0) (98.7) (90.6)
Sex, n (%)
Female 440,901 (48.3) 963 257 5945 51 331,152 (51.7) 37,861 3086 116,348 1470
(83.8) (79.1) (69.1) (40.2) (90.4) (82.8) (75.4) (43.5)
Male 471,227 (51.7) 186 68 2661 76 309,260 (48.3) 4043 (9.6) 639 37,907 1907
(16.2) (20.9) (30.9) (59.8) (17.2) (24.6) (56.5)
Concurrent autoimmune 27,895 (3.1) 224 62 992 10 (7.9) 22,009 (3.5) 6630 670 27,750 342
condition, n (%) (19.5) (19.1) (11.5) (15.8) (18.0) (18.0) (10.1)
Comorbidity, n (%)d
Myocardial infarction 2225 (0.2) 3 (0.3) 6 (1.8) 70 (0.8) 2 (1.6) 476 (0.1) 115 (0.3) 23 (0.6) 545 (0.4) 21 (0.6)
Congestive heart failure 6775 (0.7) 14 (1.2) 15 (4.6) 317 (3.7) 13 1433 (0.2) 440 (1.1) 160 (4.3) 2138 (1.4) 127 (3.8)
(10.2)
Peripheral vascular disease 1953 (0.2) 15 (1.3) 7 (2.2) 176 (2.0) 1 (0.8) 1273 (0.2) 474 (1.1) 71 (1.9) 2047 (1.3) 65 (1.9)
Cerebrovascular disease 21,027 (2.3) 53 (4.6) 20 (6.2) 820 (9.5) 18 1787 (0.3) 787 (1.9) 115 (3.1) 2249 (1.5) 51 (1.5)
(14.2)
Chronic pulmonary disease 71,540 (7.8) 244 79 2557 35 12,335 (1.9) 2196 (5.2) 248 (6.7) 8035 (5.2) 167 (4.9)
(21.2) (24.3) (29.7) (27.6)
Rheumatol Ther (2023) 10:387–404
Table 1 continued
Patients, Variable Taiwana USAb
General SLE RA pMN General SLE RA pMN
population ERL LN populationc ERL LN

Dementia 2250 (0.2) 5 (0.4) 4 (1.2) 97 (1.1) 3 (2.4) 229 (0.0) 24 (0.1) 6 (0.2) 257 (0.2) 3 (0.1)
Hemiplegia or paraplegia 2434 (0.3) 4 (0.3) 0 (0) 86 (1.0) 0 (0) 363 (0.1) 83 (0.2) 21 (0.6) 194 (0.1) 6 (0.2)
Diabetes 23,189 (2.5) 49 (4.3) 32 (9.8) 1064 24 12,892 (2.0) 1797 (4.3) 314 (8.4) 10,652 324 (9.6)
Rheumatol Ther (2023) 10:387–404

(12.4) (18.9) (6.9)

Diabetes with chronic 14,021 (1.5) 15 (1.3) 19 (5.8) 456 (5.3) 15 1307 (0.2) 196 (0.5) 78 (2.1) 1398 (0.9) 89 (2.6)
complications (11.8)
Mild liver disease 32,916 (3.6) 160 48 1532 21 40 (1.2) 1698 (1.1) 71 (1.9) 1375 (0.2) 71 (1.9)
(13.9) (14.8) (17.8) (16.5)
Moderate to severe liver 1068 (0.1) 3 (0.3) 2 (0.6) 22 (0.3) 1 (0.8) 48 (0.0) 26 (0.1) 6 (0.2) 42 (0.0) 1 (0.0)
disease
Peptic ulcer disease 58,116 (6.4) 255 76 3097 39 460 (0.1) 7 (0.0) 11 (0.3) 120 (0.1) 345
(22.2) (23.4) (36.0) (30.7) (10.2)
Medications, n (%)e
Systemic steroids 127,709 (14.0) 615 207 3023 75 76,593 (12.0) 20,763 2449 84,538 1318
(53.5) (63.7) (35.1) (59.1) (49.5) (65.7) (54.8) (39.0)
Biologics 0 (0) 0 (0) 0 (0) 23 (0.3) 0 (0) 703 (0.1) 423 (1.0) 53 (1.4) 29,418 22 (0.7)
(19.1)
Calcineurin inhibitors 112 (0) 10 (0.9) 15 (4.6) 63 (0.7) 16 2036 (0.3) 1380 (3.3) 180 (4.8) 2417 (1.6) 467
(12.6) (13.8)
mTOR inhibitors – – – – – 13 (0) 8 (0) 8 (0.2) 2 (0) 13 (0.4)
Cytostatic and 533 (0.1) 51 (4.4) 78 782 (9.1) 19 746 (0.1) 2625 (6.3) 255 (6.8) 57,979 148 (4.4)
antiproliferative (24.0) (15.0) (37.6)
395
396 Rheumatol Ther (2023) 10:387–404

aHR 0.6, 95% CI 0.5–0.9; RA, aHR 0.5, 95% CI

ERL extra-renal lupus, LN lupus nephritis, MDH malate dehydrogenase, mTOR mechanistic target of rapamycin, pMN primary membranous nephropathy, RA
328 (9.7)

Comorbidities assessed that are part of the Charlson Comorbidity Index, omitting conditions that were specified as part of the inclusion/exclusion study criteria
Post-index medications for systemic steroids considered as those that were administered orally or via intravenous/intramuscular injection. Overall immunosup-
0.4–0.6; primary membranous nephropathy,

pMN
aHR 0.7, 95% CI 0.4–1.1). We also identified
significantly increased aHRs for serious infec-

9509 (6.2)
tions among patients with comorbid conditions
and among those who received post-index sys-
temic steroids and/or immunosuppressants
RA

(38.2) (ESM Fig. S2).

3212 (7.7) 1424

Comparison of Patients with SLE and RA

LN

Identified via the One Million General

Sample Database and the Catastrophic

pressant use includes biologics, calcineurin inhibitors, mTOR inhibitors, cytostatic and antiproliferative or MDH inhibitor
Illness Database in Taiwan
ERL
SLE

Among patients with SLE and RA identified via

diagnostic algorithms within the OMGSD, we
identified 27% (403/1474) of the SLE patients
populationc

477 (0.1)

and 10.5% (904/8606) of the RA patients who

General
USAb

were also captured in the CID (403/1474) based

on unique patient-level identifiers. Among
patients with certified catastrophic illness, there
Truven Healthcare MarketScanÒ Commercial Claims and Medicare databases (2000–2012)

were a higher proportion of pediatric cases,

118 (1.4) 7 (5.5)
pMN

1 million sample from National Health Insurance Research Database (2000) in Taiwan

more concurrent autoimmune conditions and

more patients with a claim for post-index sys-
temic steroids and/or immunosuppressants
rheumatoid arthritis, SD standard deviation, SLE systemic lupus erythematosus

compared with patients identified via the study-

RA

derived algorithm in the OMGSD. ESM Table s7

provides a detailed description of the patients
(25.8)

with SLE and RA identified in Taiwan via the

1 million random sample selected for U.S. general population only
LN

OMGSD only compared with those patients

84

who also received certification of their condi-

89 (7.7)

tion and were present in the CID. The estimated

ERL

standardized incidence ratios (SIRs) for patients

SLE

with SLE and RA observed in the CID were

slightly higher, but not significantly higher,
than those derived from the patients identified
population

in the OMGSD (Fig. 4).

Taiwana
General

131 (0)

DISCUSSION
Findings from this large multinational retro-
spective claims-based cohort study confirm the
important role of infections among patients
Table 1 continued
Patients, Variable

with autoimmune conditions. We identified

MDH inhibitors

significant excess rates of serious infection

among patients with SLE (particularly among
those with lupus nephritis), RA and primary
membranous nephropathy compared with the
general population in both Taiwan and the
d
b
a

e
Table 2 Serious infections in Taiwan and the USA by patient cohort
Patients, Variable Taiwana USAb
General SLE RA pMN General SLE RA pMN
population ERL LN population ERL LN
n 9,12,302 1149 325 8606 127 6,40,412 41,904 3725 1,54,255 3377
Standardized SI rate (95% CI), per 22.7 43.4 215.3 70.6 28.7 2.6 21 63.3 15.6 9
1000 person-yearc (22.4, 23.1) (42.9, (214.3, (70.1, (28.3, 29.0) (2.4, 2.7) (20.6, (62.7,63.9) (15.3, (8.7,
Rheumatol Ther (2023) 10:387–404

43.8) 216.3) 71.2) 21.4) 15.9) 9.2)

SIs (composite)d 20,742 (2.3) 72 (6.3) 83 (25.5) 383 22 (17.3) 1636 (0.3) 907 332 (8.9) 2866 138
(4.5) (2.2) (1.9) (4.1)
SI types, n (%)
Bacterial infections 8639 (0.9) 39 (3.4) 49 (15.1) 219 19 (15.0) 739 (0.1) 438 206 (5.5) 1617 89
(2.5) (1.0) (1.0) (2.6)
Diverticulitis 70 (0.0) 0 (0) 0 (0) 5 (0.1) 0 (0) 173 (0.0) 85 (0.2) 15 (0.4) 304 14
(0.2) (0.4)
Pneumonia/upper respiratory 7389 (0.8) 18 (1.6) 15 (4.6) 79 (0.9) 4 (3.1) 593 (0.1) 336 107 (2.9) 1040 29
(0.8) (0.7) (0.9)
Skin and soft tissue 2417 (0.3) 8 (0.7) 12 (3.7) 68 (0.8) 5 (3.9) 314 (0.0) 174 42 (1.1) 566 38
(0.4) (0.4) (1.1)
Pyelonephritis/urinary tract 4823 (0.5) 21 (1.8) 27 (8.3) 105 9 (7.1) 209 (0.0) 122 48 (1.3) 435 16
infection (1.2) (0.3) (0.3) (0.5)
Herpes zoster 160 (0.0) 5 (0.4) 9 (2.8) 3 (0.0) 2 (1.6) 1266 (0.2) 373 82 (2.2) 984 37
(0.9) (0.6) (1.1)
Opportunistic 1067 (0.1) 14 (1.2) 15 (4.6) 28 (0.3) 5 (3.9) 18 (0.0) 19 (0.0) 18 (0.5) 70 (0.0) 5 (0.1)
Viral hepatitis 978 (0.1) 7 (0.6) 7 (2.2) 24 (0.3) 0 (0) 9 (0.0) 2 (0.0) 0 (0) 6 (0.0) 0 (0)
397
398 Rheumatol Ther (2023) 10:387–404

USA, driven largely by bacterial, respiratory,

Within-setting standardization. Within each location, patient cohorts were standardized to their general population using direct standardization based on age, sex,
pMN

0 (0)
urinary tract and opportunistic infections,
which is consistent with prior findings
[7, 36–44].

0 (0)
We strove to use a standard methodological
RA

approach and similar real-world data systems

across cohorts from both Taiwan and the USA.
The OMGSD and the MarketScan CC and
0 (0)

Medicare Supplemental databases are insurance

LN

claims systems that use the same diagnostic

classification system (ICD-9) to enhance simi-
larity between the setting-specific findings. We
0 (0)
ERL
SLE

further assessed our findings based on identifi-

cation of patients with a diagnostic algorithm
compared with identification of patients with a
Composite SIs excluded viral hepatitis because this was considered a secondary cause of membranous nephropathy
population

catastrophic illness certified by rheumatologists

General

in Taiwan. Although we identified heightened

USAb

0 (0)

rates of serious infections among patients with

SLE and RA compared with the general popu-
lation in Taiwan, regardless of whether or not
patients had received a catastrophic illness cer-
pMN

0 (0)

Truven Healthcare MarketScanÒ Commercial Claims and Medicare databases (2000–2012)

tification, we did observe higher post-index

index year, pre-existing serious infection and systemic steroid and immunosuppressant use

systemic steroid and immunosuppressant use

1 million sample from National Health Insurance Research Database (2000) in Taiwan

among patients in the CID (particularly among

0 (0)

RA patients), which did not result in significant

RA

differences in the estimated serious infection

rates. This suggests that such patients may have
1 (0.3)

more severe disease and/or have greater access

to medications because of lower out-of-pocket
LN

costs.
Although we standardized our approach and
0 (0)
ERL
SLE

chose the respective data systems to maximize

similarities, there remained inherent differences
between the Taiwan and U.S. populations and
population

healthcare systems that are important to con-

Taiwana
General

sider and which limit direct comparisons of our

15 (0)

findings, such as differences in underlying

CI Confidence interval, SI serious infection

sociodemographic factors, disease endemicity

and potential differences in coding conventions
and healthcare systems. Whereas the age and
gender distribution of the identified general
population cohort was comparable between
Taiwan and the USA, there were important dif-
ferences in the distribution of underlying
Table 2 continued

comorbidities (particularly cerebrovascular,

Patients, Variable

chronic pulmonary, liver and peptic ulcer dis-

Tuberculosis

ease). There are also notable differences in the

endemicity of specific infectious diseases
between Taiwan and the USA (e.g. hepatitis,
tuberculosis, opportunistic infections) that may
d
b
a

c
Rheumatol Ther (2023) 10:387–404
Fig. 3 Within-setting comparisons of serious infection
rates for autoimmune patients versus the general popula-
tion. Adjusted SIRs and 95% CIs of serious infection rates
for autoimmune patients (extra-renal lupus, lupus
have influenced our findings [45, 46]. Longitu-
dinal follow-up of patient records is more
comprehensive in Taiwan than in the USA
because Taiwan has a single-payer system that
follows patients from birth to death (closed
system), whereas insurance claims for U.S.
patients may be incomplete due to a multi-
payer system that results in potential enroll-
ment changes over time due to changes in
healthcare insurance coverage (dynamic sys-
tem). The differential follow-up between the
claims data from the two settings may have led
399
nephritis, RA and pMN) were compared with the general
population by setting. CI Confidence interval, SI serious
infection, SIR standardized incidence ratio
to index dates that are earlier in the course of
disease for autoimmune conditions among
patients from Taiwan relative to U.S. patients.
Greater subsidization of healthcare costs in
Taiwan may have influenced patient behavior
and subsequent capture of illness and/or medi-
cation in the patient records. In fact, in our
study, patients from Taiwan had an average of
12 doctor visits per patient per year compared
with four visits per year among U.S. patients.
Such differences in healthcare-seeking behavior,
as well as differences in medication approval
400
Fig. 4 Estimated SIRs of patients from Taiwan with SLE
and RA in the OMGSD and CID. Adjusted SIRs and 95%
CIs of serious infection rates for patients with SLE and RA
compared with the general population by database
(OMGSD and CID) in Taiwan. CID Catastrophic Illness
Database, OMGSD One Million General Sample Database
and coverage, in particular the limited use of
biologics in Taiwan, may have influenced our
findings [47]. Furthermore, even though we
used standard algorithms to identify patients
and infections, it is possible that coding prac-
tices differed slightly between the two settings.
This study provides a unique assessment of
SIRs among patients with autoimmune condi-
tions receiving standard-of-care treatments in
routine clinical practice based on insurance
claims data from different geographical regions.
We provide estimated SIRs overall and by
infection subtype, accounting for the potential
influence of important demographic and clini-
cal factors in a study period spanning over a
decade. We provide a novel assessment of SIRs
compared with the general population in Tai-
wan based on the OMGSD and the CID data-
bases that resulted in comparable estimates for
patients with SLE and RA and provide an indi-
rect assessment of the accuracy of our findings
using an algorithm based on diagnostic coding.
Overall, we observed heightened aHRs for seri-
ous infections among patients who received
Rheumatol Ther (2023) 10:387–404
systemic steroids and immunosuppressants;
however, the influence of these medications
across type of autoimmune patient and setting
was variable (ESM Fig. S2). Specifically, systemic
steroid use in the first year post-index results in
heightened aHRs of serious infection, while we
did not identify similar findings among patients
who received immunosuppressants in the first
year post-index. While estimated aHRs for seri-
ous infections among autoimmune patients
who received immunosuppressants were vari-
able and fairly imprecise, the findings may have
resulted from our assessment of serious infec-
tions in the first year post-index and may reflect
an individual patient’s condition, routing
treatments in the early stages of a patient’s
disease, variable treatment practices across set-
tings and patient groups, as well as variable
accuracy of index date between systems as a
result of variable follow-up of patients’ health-
care records. Further, these discrepant findings
may have resulted from different prescribing
patterns based on dosage, patient population
and disease severity and/or duration, which
were not captured in our study and may have
differed between the two settings. Additional
limitations of our study include the relatively
small size of the study population from Taiwan,
which limited the number of patients identified
with rare conditions, such as primary membra-
nous nephropathy, as well as the inability to
identify serious infections that result in death
due to the lack of available mortality data
within claims databases. The use of algorithms
based on diagnostic and procedural codes
within insurance claims data may have limited
our ability to identify and classify patient health
status, as well as to ascertain potentially
important intrinsic and extrinsic factors that
were not captured in this type of real-world data
[48–50].
CONCLUSIONS
In conclusion, this unique large real-world data
study provides estimates of SIRs for patients
with SLE, RA and primary membranous
nephropathy receiving standard-of-care treat-
ment and confirms significantly heightened
Rheumatol Ther (2023) 10:387–404
serious infection rates among such patients
compared with the general population in both
Taiwan and the USA. These findings provide
evidence that can facilitate treatment decisions
for patients and aid in the development and
introduction of new immune-targeted
therapeutics.
ACKNOWLEDGEMENTS
Funding. This work was funded by Genen-
tech, Inc. a member of the Roche Group. The
publication of this article along with the jour-
nal’s Rapid Service Fee was funded by Genen-
tech, Inc.
Medical Writing, Editorial, and Other
Assistance. Support for third-party medical
writing/editorial assistance, furnished by Nicola
Gillespie, DVM, of Health Interactions, Inc., was
provided by Genentech, Inc.
Authorship. All named authors meet the
International Committee of Medical Journal
Editors (ICMJE) criteria for authorship for this
article, take responsibility for the integrity of
the work as a whole, and have given their
approval for this version to be published.
Author Contributions. Lisa Lindsay, Ching-
Yi Chuo and Wen-Nan Huang wrote the main
manuscript text. Ching-Yi Chuo prepared the
figures. Wei-Szu Lin and Ching-Yi Chuo con-
ducted the statistical analyses. Lisa Lindsay,
Ching-Yi Chuo, Wen-Nan Huang, Katie Tuck-
well, Nicholas S. Jones, Joshua Galanter, Ching-
Heng Lin and Yi-Ming Chen contributed to the
study protocol and reviewed the manuscript.
Disclosures. Lisa Lindsay, Nicholas S. Jones
and Joshua Galanter are employed by and hold
shares in Genentech, Inc., a member of the
Roche Group. Ching-Yi Chuo and Katie Tuck-
well were employees and shareholders of
Genentech, Inc. at the time the research was
conducted. Ching-Yi Chuo’s current affiliation
is Gilead Sciences. Katie Tuckwell’s current
affiliation is Regeneron. Wen-Nan Huang,
401
Ching-Heng Lin, Yi-Ming Chen and Wei-Szu
Lin have nothing to disclose.
Compliance With Ethics Guidelines. The
protocol for this study is in line with the 2008
Declaration of Helsinki and its subsequent
amendments. The authors conducted secondary
research using de-identified U.S. data licensed
from IBMÒ WatsonÒ question-answering com-
puter system in compliance with U.S. Code of
Federal RegulationsTitle 45 (45 CFR) Sec-
tion 164.514(a–c) and the National Health
Insurance Program in Taiwan. The data from
both the USA and Taiwan had identifying
information removed and were coded in such a
way that the data could not be linked back to
subjects from whom it was originally collected.
This research does not require Institutional
Review Board or ethics review, as analyses with
these data do not meet the definition of ‘‘re-
search involving human subjects,’’ defined as
living individuals about whom an investigator
obtains identifiable private information for
research purposes. Furthermore, use of claims
data from Taiwan included in this research was
approved by the Taichung Veterans General
Hospital Institutional Review Board I and II
(CE13152B-8). Neither the provider of the data
nor the researchers were able to link the data
with identifiable individuals. Consent to par-
ticipate was not applicable in this retrospective
observational study of de-identified data.
Data Availability. The datasets analyzed
during the current study are not publicly avail-
able due to restrictions that apply to the avail-
ability of these data available from Merative
(previously IBMÒ WatsonÒ) and the National
Health Insurance Program in Taiwan.
Open Access. This article is licensed under a
Creative Commons Attribution-NonCommer-
cial 4.0 International License, which permits
any non-commercial use, sharing, adaptation,
distribution and reproduction in any medium
or format, as long as you give appropriate credit
to the original author(s) and the source, provide
a link to the Creative Commons licence, and
indicate if changes were made. The images or
other third party material in this article are
402
included in the article’s Creative Commons
licence, unless indicated otherwise in a credit
line to the material. If material is not included
in the article’s Creative Commons licence and
your intended use is not permitted by statutory
regulation or exceeds the permitted use, you
will need to obtain permission directly from the
copyright holder. To view a copy of this licence,
visit http://creativecommons.org/licenses/by-
nc/4.0/.
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