Received: 10 October 2018  | Revised: 8 January 2019  | Accepted: 22 January 2019

DOI: 10.1111/1756-185X.13511

ORIGINALARTICLE

Real‐world effectiveness and safety of rituximab in the

treatment of rheumatoid arthritis: A single‐center
experience in Taiwan
1,2 1,2,3 1,2
Kai‐Chun Wang  | Hsien‐Tzung Liao  | Wei‐Sheng Chen | Chien‐Chih
1,2,4 1,2 1,2 1,2
Lai  | Chung‐Tei Chou | Ming‐Han Chen  | Chang‐Youh Tsai

1
Division of Allergy, Immunology and
Rheumatology, Department of Medicine,
Abstract
Taipei Veterans General Hospital, Taipei,
Aim: To assess the real‐world effectiveness and safety of rituximab (RTX) at 24
Taiwan
2
Faculty of Medicine, National Yang‐Ming months in patients with established rheumatoid arthritis (RA) and to identify pre‐
University School of Medicine, Taipei, dictors of low disease activity/remission and a good European League Against
Taiwan
Rheumatism (EULAR) response.
3
Division of Allergy, Immunology and
Rheumatology, Department of Internal Methods: Seventy RTX‐treated RA patients were enrolled. Predictors for low
Medicine, School of Medicine, College of disease activity/remission and a good EULAR response at 24 months were identified
Medicine, Taipei Medical University, Taipei,
Taiwan by mul‐ tivariate analyses.
4
Institute of Clinical Medicine, National Results: At 24 months, the mean Disease Activity Score of 28 joints—erythrocyte
Yang‐Ming University School of Medicine,
Taipei, Taiwan sedimentation rate (DAS28‐ESR) decreased from 6.88 ± 0.85 at baseline to 3.47 ±
0.85. Twenty‐nine patients (41.4%) reached low disease activity/remission, while all
Correspondence
Ming‐Han Chen and Chang‐Youh Tsai,
patients had a moderate/good EULAR response. After adjustment by multi‐ variate
Division of Allergy, Immunology, and analyses, we found concomitant methotrexate at a dosage >10 mg/week (odds ratio
Rheumatology, Department of Medicine,
Taipei Veterans General Hospital, Taipei
[OR] 5.17; 95% CI 1.34‐19.93; P = 0.017) predicted low disease activity/ remission,
City, Taiwan. and baseline DAS28 ≤6.5 (OR 4.97; 95% CI 1.22‐20.30; P = 0.026) pre‐ dicted
Emails: mhchen6@vghtpe.gov.tw; cytsai@
good EULAR response at 24 months. The most common adverse events were
vghtpe.gov.tw
infusion‐related (5.7%), and there was no incidence of malignancy or mortality
during the treatment.
Conclusions: RTX was effective and safe in real‐life management of RA patients
with high disease activity. Patients taking concomitant methotrexate and with lower
base‐ line DAS28‐ESR were more likely to benefit from RTX.

KEYWORDS
CD20, DAS‐28, rheumatoid arthritis, rituximab

1 | INTRODUCTION
Rheumatoid arthritis (RA), a systemic autoimmune disease targeting
synovial tissues, causes longstanding inflammation and catastrophic
sequelae in multiple joints. The resultant progressive deformity and
physical disability impair quality of life. Conventional synthetic disease‐
modifying antirheumatic drugs (csDMARDs) are the primary treatment
strategy for RA, among which methotrexate (MTX) is the cornerstone
unless contraindicated or not tolerated. Short‐term glucocorticoids would
be bridging therapy when switching csDMARDs. Biologic DMARDs
(bDMARDs) and targeted synthetic DMARDs (tsDMARDs) can be added
1
to csDMARDs when remission cannot be achieved.
A presence of rheumatoid factor (RF) and/or anti‐citrullinated
protein antibody (ACPA) could be detected years before onset of

Int J Rheum Dis. 2019;1–9. wileyonlinelibrary.com/journal/apl © 2019 Asia Pacific League of Associations for   |  1
Rheumatology and John Wiley & Sons Australia, Ltd
2  | WANG
2
clinical symptoms of RA, and their titers have been shown to pre‐
dict functional and radiological outcomes. In addition to producing
these antibodies, B cells are also highly efficient in antigen presen‐
tation and can activate auto‐reactive T cells. Rituximab (RTX), a
bD‐ MARD of chimeric murine/human monoclonal antibody
targeting CD20‐positive B cells, has thus been proven effective in
randomized clinical trials (RCTs) in patients with active established
RA resistant to csDMARDs and anti‐tumor necrosis factor α (anti‐
3-5
TNFα) bD‐ MARDs. A single course of RTX with two 1000 mg
infusions given 2 weeks apart significantly ameliorates disease
burden. As shown previously, at week 24, 51% of patients had an
American College of Rheumatology 20% improvement (ACR20)
response, 50% of pa‐ tients had a European League Against
Rheumatism (EULAR) mod‐ erate response and 15% of patients
5
had a EULAR good response. However, the populations in RCTs
may not accurately reflect the characteristics of the real‐world
patients as strict inclusion and ex‐ clusion criteria were applied to
increase the internal validity but not external generalizability. A
systemic review has demonstrated that characteristics of patients
from real‐world observational studies are substantially different from
6
those enrolled in RCTs, leading to an efficacy‐effectiveness gap.
As a result, the real‐world evidence is vital because it is not only
generated from investigations of hetero‐ geneous populations with
diverse behaviors in routine practices, but also can validate the
results in RCTs. Nevertheless, most of the RCTs and observational
studies showing outcomes of RTX treatments have been conducted
in Western countries and very few studies have examined the
7,8
effectiveness and safety of RTX for RA in ethnic Asians.
Several authors have also attempted to identify specific pre‐
dictive factors for RTX treatment response in RA patients to help
clinical rheumatologists take a more personalized and precise thera‐
peutic approach. The presence of RF and/or ACPA, number of
previ‐ ous bDMARDs, baseline Disease Activity Score of 28 joints
(DAS28), serum immunoglobulin level and biomarkers including type
I in‐ terferon and myeloid‐related protein (MRP)8/14 levels, have
9 and their improvement from the baseline. The clinical remission
been shown to affect treatment responses in previous studies. On
the other hand, a low body mass index has not yet been proven to
be a reliable index to predict RTX effectiveness although it has been
10
used so in anti‐TNFα therapy.
Due to lack of studies addressing the real‐life outcomes of RA
patients undergoing RTX therapy in Asia, we carried out the pres‐
ent investigation to characterize the real‐world use, effectiveness,
and safety of RTX in patients with RA. Furthermore, we identified
possible predictors for achieving low disease activity/remission or a
EULAR good response in these RTX‐treated RA patients at 24
months of treatment.
2 | PATIENTS AND METHODS
2.1 | Patients
In the present retrospective study, we enrolled 70 adult patients with
RA who underwent RTX treatment at the Allergy, Immunology and
et al.
Rheumatology Division in Taipei Veterans General Hospital, a ter‐ tiary
referral center in Taiwan, from October 2008 to January 2016. All
patients fulfilled the ACR 1987 revised criteria or ACR/EULAR 2010
11,12
criteria for RA classification, and had previously failed standard
csDMARDs. There were no disease activity or comorbid‐ ity exclusion
criteria. All patients received RTX as accredited by this country's health
administration in a 6‐month fixed repetitive proto‐ cols (two 1000 mg
intravenous doses, 14 days apart) as the 2nd line bDMARD with the
reasons for switching to RTX being recorded. This study was approved
by the institutional ethics committee of Taipei Veterans General Hospital
(IRB‐TPEVGH No. 2017‐05‐002AC).
2.2 | Clinical evaluations and laboratory tests
Clinical parameters including 28 tender joint count (TJC), 28 swol‐
len joint count (SJC), and DAS28 using erythrocyte sedimentation
rate (DAS28‐ESR) were assessed at baseline and at 6, 12, 18 and
24 months after initiating RTX. The numbers and types of the previ‐
ous anti‐TNFα agents, and numbers and dosages of the
concomitant DMARDs and glucocorticoids were also documented.
Laboratory tests including ESR, RF and ACPA were periodically
assessed. RF was examined using nephelometry (Toshiba TBA™‐
c16000 device, Toshiba Medical Systems Corporation, Tochigi‐ken,
Japan; positive if >30 IU/mL) and ACPA was measured using
enzyme‐linked immuno‐ sorbent assay (Phadia EliA™ kit, Phadia
AB, Uppsala, Sweden; posi‐ tive if >10 U/mL).
2.3 | Definition of clinical response and remission
The clinical remission status was defined by DAS28‐ESR ≤2.6, low
disease activity by DAS28‐ESR >2.6 but ≤3.2, moderate disease
activity by DAS28‐ESR >3.2 but ≤5.1 and high disease activity by
DAS28‐ESR >5.1. Responses to RTX therapy were assessed using
13
the EULAR criteria. Patients were classified as responders (good
or moderate) or non‐responders according to DAS28‐ESR levels
status and responses were evaluated at 6, 12, 18 and 24 months
after the 1st dose of RTX.
2.4 | Safety issues
Adverse events including infusion reactions, infections, serious in‐
fections necessitating admission, malignancies, and mortalities were
recorded.
2.5 | Statistical analysis
The baseline characteristics were compared with the Chi‐squared
test or Fisher's exact test for categorical variables and compared
with Mann‐Whitney U tests for the quantitative variables. DAS28‐
ESR, ESR, TJC and SJC were compared with corresponding values
at baseline using the paired sample t test. Univariate logistic regres‐
sion was performed to identify predictive factors for the low disease
WANG et al.      |  3
TA B LE 1 Demography and characteristics of RA patients (CI). A P value <0.05 was considered significant. Data were
undergoing rituximab therapy analyzed with SPSS software, version 22 (IBM, Armonk, NY, USA).

RA patients
Characteristics (n = 70) 3 | RESULTS
Female gender, n (%) 67 (95.7)
Age at diagnosis, mean (SD), y 54.1 (10.6) 3.1 | Demographic and clinical characteristics
Age at RTX initiation, mean (SD), y 58.9 (10.6)
A total of 70 patients, including 67 women (95.7%), were en‐ rolled
Disease duration, mean (SD), y 4.9 (1.8)
in this study. The mean age at RTX initiation was 58.9 years.
Baseline TJC, mean (SD), n 16.5 (4.8)
Demographic characteristics of patients are shown in Table 1. At
Baseline SJC, mean (SD), n 9.7 (4.8) baseline, patients had a mean disease duration of 4.9 years and a
Baseline ESR, mean (SD), mm/h 59.1 (33.6) sig‐ nificant disease burden with a mean DAS28‐ESR high at 6.88 ±
Baseline DAS28‐ESR, mean (SD) 6.88(0.85) 0.85, mean SJC of 9.7 ± 4.8, and mean TJC of 16.5 ± 4.8. Four
RF positive, n (%) 63 (90.0) patients (5.7%) overlapped with systemic lupus erythematosus, 20
ACPA positive, n/total (%) 38/69 (55.1) patients (28.6%) had Sjögren's syndrome, and 7 patients (10%) had

Comorbidity, n (%)
interstitial lung disease at baseline.

Systemic lupus erythematosus 4 (5.7) Sixty‐six patients (94.3%) had previously used at least 1 anti‐
TNFα agent. The remaining 4 patients took RTX as the first‐line bD‐
Sjögren's syndrome 20 (28.6)
MARD due to history of malignancy (3 had breast cancer and 1 had
Interstitial lung disease 7 (10.0)
schwannoma). During the 24 months of RTX treatment, 69 patients
Number(s) of previous anti‐TNFα, n (%)
(98.6%) received at least 1 concomitant csDMARDs including MTX,
None 4 (5.7)
leflunomide, sulfasalazine, hydroxychloroquine, and cyclosporine; in
One 59 (84.3)
average, 1.9 types of DMARDs were used. Forty‐nine patients
≥2 7 (10.0) (70.0%) received MTX during the 24 months at a mean dosage of
Item(s) of previous anti‐TNFα (specified), n (%) 10.71 ± 3.85 mg/wk. There were also 26 patients (37.1%) taking
Etanercept 49 (74.2) prednisolone along with RTX at a mean dosage of 7.69 ± 2.60 mg/d.
Adalimumab 10 (15.2)
Etanercept and adalimumab 7 (10.6) 3.2 | Improvement of laboratory and
Concomitant medication in 24 mo
clinical parameters by RTX
csDMARDs, mean (SD), n 1.9 (0.6)
csDMARDs other than MTX, mean (SD), n 1.2 (0.6) After initiation of RTX, we observed a significant improvement of mean
DAS28‐ESR at 6, 12, 18, 24 months as compared with baseline levels
MTX usage, n (%) 49(70.0)
(P < 0.001 for each comparison), and the mean decrement of DAS28‐
MTX dosage, mean (SD), mg/wk 10.71 (3.85)
ESR at 24 months was 3.41 ± 0.93 (Figure 1A). The mean ESR level at
Mean ≤7.5 mg/wk, n/total (%) 25/49 (51.0) 24 months significantly decreased when compared to that at baseline
Mean ≤10 mg/wk, n/total (%) 28/49 (57.1) (19.7 ± 17.3 vs 59.1 ± 33.6; P < 0.001; Figure 1B). Similarly, the mean
Prednisolone usage, n (%) 26 (37.1) SJC and TJC were also significantly lower at 24 months, compared to
those at baseline (P < 0.001, P < 0.001, respectively; Figure 1C,D).
Mean prednisolone dosage, mean (SD), mg/d 7.69 (2.6)
All patients were in high disease activity at baseline. After 24 months,
ACPA, anti‐citrullinated protein antibody; CRP, C‐reactive protein; csD‐
none were in high disease activity: 12 patients (17.1%) achieved
MARDs, conventional synthetic disease‐modifying anti‐rheumatic drugs;
DAS28‐ESR, Disease Activity Score of 28 joints—erythrocyte sedimen‐ remission, 17 patients (24.3%) reached low disease activity, and 41
tation rate; ESR, erythrocyte sedimentation rate; MTX, methotrexate; RF, patients (58.5%) had moderate disease activity (Figure 2A).
rheumatoid factor; RTX, rituximab; SD, standard deviation; SJC, swollen
joint count; TJC, tender joint count; TNF, tumor necrosis factor.
3.3 | Predictors for clinical remission at 24 months
activity/remission and good EULAR responders at 24 months. Variables
with a P value ≤0.15 in the univariate analysis were taken into Comparing the 41 patients (58.5%) with moderate disease ac‐ tivity
multivariate logistic regression models using backward selec‐ tions to to the 29 patients (41.4%) with low disease activity/re‐ mission at 24
estimate odds ratios (ORs) for clinical remission status and EULAR months, those who were in low disease activity/ remission at 24
responses. The multivariate models were also adjusted for age, gender, months had a longer duration of disease (5.3 ± 2.1 vs 4.6 ± 1.4
and known predictive factors for RTX response accord‐ ing to a literature years; P = 0.041), and a significantly greater proportion of them took
review, which included the presence of RF and/or ACPA, baseline concomitant MTX at a mean dosage >10 mg/wk (59.1% vs 29.6%; P
9
DAS28‐ESR levels, and numbers of previous biolog‐ ics. Results are = 0.038; Table S1). There were no significant differences in age at
diagnosis, age at RTX initiation, gender, TJC, SJC, DAS28‐ESR,
expressed as ORs with a 95% confidence interval
4  | WANG et al.

FI G U R E 1 Changes in clinical and laboratory parameters in 70 patients with rheumatoid arthritis treated with rituximab, at baseline, 6, 12,
18, and 24 mo. (A) The Disease Activity Score of 28 joints‐ erythrocyte sedimentation rate (DAS28‐ESR) levels; (B) ESR; (C) swollen joint
count (SJC); (D) tender joint count (TJC). All parameters were significantly lower than the corresponding baseline levels (P < 0.001)

presence of RF, presence of ACPA, autoimmune comorbidities, pro‐
portion of no more than 1 previous anti‐TNFα, refractoriness to anti‐
TNFα, and concomitant uses of csDMARDs and prednisolone.
We then used univariate logistic regression to find predictors for low
disease activity/remission at 24 months of RTX therapy. It was identified
that a concomitant MTX use (OR 1.17; 95% CI 1.002‐1.37; P = 0.047),
especially at a level of more than 10 mg/week (OR 3.43; 95% CI 1.05‐
11.22; P = 0.041) was a predictor for low disease activity/ remission
(Table 2). The multivariate logistic regression model, which was adjusted
for gender, age, disease duration, DAS28‐ESR level, pres‐ ence of
RF/ACPA, no more than 1 previous anti‐TNFα, and concomitant
prednisolone usage revealed the correlation between concomitant mean
MTX dosage of more than 10 mg/wk and low disease activity/re‐ mission
at 24 months (OR 5.17; 95% CI 1.34‐19.93; P = 0.017; Table 2).
13
(17.1%) and 58 moderate responders (82.9%). The good
respond‐ ers had a longer disease duration (5.5 ± 1.2 vs 4.8 ± 1.8
years; P = 0.043), lower baseline DAS28‐ESR levels (41.58 ± 33.30
vs 62.72 ± 32.75; P = 0.043), and a baseline DAS28‐ESR ≤6.5
(66.7% vs 25.9% of respective cohort; P = 0.014; Table S2). No
significant differences were observed between good and moderate
respond‐ ers regarding the age at diagnosis, age at RTX initiation,
gender, TJC, SJC, RF/ACPA seropositivity, autoimmune
comorbidities, concomitant use and adjustment of csDMARDs and
predniso‐ lone, previous anti‐TNFα of no more than 1 and
refractoriness to anti‐TNFα.
We analyzed global DAS28‐ESR as well as categorized DAS28‐
ESR at 6, 6.5 and 7 using univariate logistic regression to identify
predictors of a good EULAR response and found that global DAS28 ‐
ESR (OR 0.28; 95% CI 0.11‐0.69; P = 0.005) and categorization of

3.4 | Predictors for EULAR response at 24 months DAS28‐ESR ≤6.5 (OR 5.73; 95% CI 1.51‐21.82; P = 0.001) were good
predictors. We then analyzed these data further with a multivari‐ ate
As shown in Figure 2B, all patients were EULAR responders at 24 logistic regression model, which was adjusted by gender, age, RF/ACPA
months after RTX treatment, including 12 good responders seropositivity, and number of previous anti‐TNFα ≤1, and
WANG et al.      |  5

FI G U R E 2 (A) Percentages of clinical remission status according to Disease Activity Score of 28 joints‐ erythrocyte sedimentation rate
(DAS28‐ESR) levels and (B) percentages of responses according to European League Against Rheumatism criteria at months 6, 12, 18 and
24 in 70 patients with rheumatoid arthritis receiving rituximab

found that baseline DAS28‐ESR ≤6.5 remained a statistically signifi‐
cant predictor (OR 4.97; 95% CI 1.22‐20.30; P = 0.026; Table 3).
3.5 | Safety outcomes
None of the enrolled patients discontinued RTX therapy during the
follow‐up. There were 4 events of infusion‐related reactions. One
serious infection event occurred, which was cellulitis complicated
with osteomyelitis caused by methicillin‐sensitive Staphylococcus
aureus and coagulase‐negative Staphylococcus. Thirteen patients
underwent interferon‐γ release assay (IGRA) at baseline; among
them, six patients had a positive result and two patients had an
indeterminate finding. Three out of the six patients with positive
IGRA received prophylaxis with isoniazid prior to the administration
of RTX. No reactivation of tuberculosis occurred. At baseline, nine
patients (12.9%) had chronic hepatitis B as defined by the presence
of hepatitis B surface antigen (HBsAg); no reactivation of hepatitis B
was noted within 24 months. In addition, no patient in our cohort
developed malignancy or died in the 24‐month follow‐up.
4 | DISCUSSION
In the present observational investigation from a tertiary refer‐ ral
center in Taiwan, RTX was effective in the treatment of RA pa‐
tients with high clinical disease activities regardless of response to
6  | WANG et al.

b
TA B LE 2 Predictors of low disease
Univariate OR Multivariate OR
a
Characteristics (95% CI) P value (95% CI) P value activity/remission at 24 mo

Female gender 1.44 (0.12‐16.62) 0.772 0.97 (0.04‐26.85) 0.973

Age at RTX initiation, y 0.98 (0.94‐1.03) 0.407 0.99 (0.91‐1.07) 0.752
Disease duration, y 1.25 (0.93‐1.68) 0.145 1.40 (0.97‐2.02) 0.076
DAS28‐ESR 0.58 (0.32‐1.06) 0.076 0.54 (0.19‐1.59) 0.265
RF positive 0.49 (0.10‐2.40) 0.381 0.12 (0.01‐1.28) 0.078
ACPA positive 1.47 (0.56‐3.90) 0.437 1.09 (0.26‐4.57) 0.904

Previous anti‐TNFα ≤1 0.94 (0.19‐4.54) 0.936 2.90 (0.20‐41.48) 0.432

Refractory to anti‐TNF‐α 0.57 (0.13‐2.51) 0.455
Concomitant medication in 24 mo
csDMARDs, n 1.25 (0.58‐2.70) 0.566
csDMARDs excluding 0.96 (0.43‐2.18) 0.929
MTX, n
MTX usage 1.63 (0.56‐4.74) 0.37
*
Mean dosage of MTX, mg/wk 1.17 (1.002‐1.37) 0.047
* *
>10 mg/wk, n/total 3.43 (1.05‐11.22) 0.041 5.17 (1.34‐19.93) 0.017
Prednisolone usage 0.39 (0.14‐1.05) 0.063 0.59 (0.13‐2.61) 0.485
Mean dosage of predniso‐ 0.84 (0.62‐1.15) 0.286
lone, mg/d

ACPA, anti‐citrullinated protein antibody; CRP, C‐reactive protein; csDMARDs, conventional syn‐
thetic disease‐modifying anti‐rheumatic drugs; DAS28‐ESR, Disease Activity Score of 28 joints—
erythrocyte sedimentation rate; ESR, erythrocyte sedimentation rate; MTX, methotrexate; RF,
rheumatoid factor; RTX, rituximab; TNF, tumor necrosis factor.
a
There are no patients with high disease activities at 24 mo.
b
Factors including age, gender, RF, ACPA, previous number of anti‐TNFα ≤1 and variables with P <
0.15 in univariate logistic regression were analyzed by multivariate logistic regression with back ‐
ward selection. ESR was excluded as it is a component of DAS28‐ESR.
*
P < 0.05

anti‐TNFα. Patients concomitantly taking MTX at a mean dosage of
more than 10 mg/wk were more likely to be in low disease activity or
remission at 24 months. For EULAR response at 24 months, patients
with a baseline DAS28‐ESR ≤6.5 were more likely to be good respond‐
ers than to be moderate responders. These outcomes were robust even
after adjustment in the multivariate logistic regression models.
The present investigation demonstrated that MTX of more than 10
mg/wk predicted lower disease activity at 24 months. These results are
important as no clinical trials have demonstrated thera‐ peutic superiority
of RTX monotherapy to combination of RTX with csDMARDs up to now,
and various clinical guidelines have recog‐ nized MTX as a preferred
csDMARD, either in itself or in combina‐ tion with other csDMARDs,
1,14
auxiliary to bDMARDs or tsDMARDs. The chimerically designed RTX
has been reported to induce anti‐ drug antibodies in 3%‐4% of RA
4
patients, which can adversely af‐ fect its efficacy, pharmacokinetics and
safety profiles. Combination with MTX may potentially decrease this
immunogenicity in a pattern similar to those seen in studies with anti‐
15
TNFα. Although this com‐ bination only predicts low disease
activity/remission but not a good EULAR response in our study, we
believe this divergence reflects the inherent differences of these
endpoints, which are composed of different factors. In addition, only
17.1% of our patients reached
a good EULAR response, in contrast to the 41.1% who reached low
disease activity/remission, which may also cause this inconsistency.
Our mean dosage of MTX has been lower than those prescribed in
Western countries, partly in that Orientals may have a poorer tol‐
erance to MTX than Caucasians. As higher dosages are commonly
not tolerated due to adverse events, the maximum dosage of MTX is
16 -18
16 mg/wk in Japan and 20 mg/wk in China. Thus, these
findings, suggesting maintaining MTX dosage above 10 mg/wk in
combina‐ tion with RTX can decrease disease activity more
effectively, are important for Orientals receiving RTX therapy.
We have also shown that patients with lower baseline DAS28‐
ESR were more likely to be good responders at 24 months. These
re‐ sults were compatible with those reported previously which
showed 2019 RA patients from the CERERRA initiative, exhibited a
lower baseline DAS28‐ESR level as a predictor of a good EULAR
19
response at 6 months. We further stratified our patients with
different base‐ line DAS28‐ESR levels (at 6, 6.5, and 7) and
confirmed with multivar‐ iate analysis that those with baseline
DAS28‐ESR ≤6.5 were more likely to be good responders.
The presence of RF and ACPA in serum has been reported to pre‐
20 -22
dict better response to RTX in previous studies. However, the
present study failed to show such correlation. The reason for this is
WANG et al.      |  7
TA B LE 3 Predictors of good EULAR a
Univariate OR Multivariate OR
response at 24 mo
Characteristics (95% CI) P value (95% CI) P value

Female gender 0.39 (0.03‐4.72) 0.461 0.25 (0.02‐4.11) 0.333

Age at RTX initiation, y 1.05 (0.98‐1.12) 0.176 1.04 (0.96‐1.12) 0.329
Disease duration, y 1.24 (0.90‐1.72) 0.192
*
Baseline DAS28‐ESR 0.28 (0.11‐0.69) 0.005
* *
DAS28‐ESR ≤6.5 5.73 0.010 4.97 (1.22‐20.30) 0.026
(1.51‐21.82)
RF positive 0.22 (0.04‐1.16) 0.075 0.20 (0.03‐1.21) 0.080
ACPA positive 1.52 (0.40‐5.78) 0.535 1.72 (0.36‐8.17) 0.494

Previous n of anti‐TNFα ≤1 0.47 (0.08‐2.78) 0.406 0.91 (0.07‐12.41) 0.941

Refractory to anti‐TNFα 0.48 (0.08‐2.81) 0.415
Concomitant medication in 24 mo
csDMARDs, n 1.01 (0.37‐2.72) 0.988
csDMARDs excluding 0.44 (0.13‐1.42) 0.168
MTX, n
MTX usage 5.79 0.104 3.72 (0.40‐34.14) 0.246
(0.70‐48.11)
MTX mean dosage, mg/wk 1.08 (0.91‐1.29) 0.390
Prednisolone usage 0.36 (0.09‐1.46) 0.151
Prednisolone mean 0.84 (0.53‐1.35) 0.475
dosage, mg/d

ACPA, anti‐citrullinated protein antibodies; csDMARDs, conventional synthetic disease‐modifying

anti‐rheumatic drugs; DAS28‐ESR, Disease Activity Score of 28 joints—erythrocyte sedimentation
rate; ESR, erythrocyte sedimentation rate; EULAR, European League Against Rheumatism; MTX,
methotrexate; RF, rheumatoid factor; RTX, rituximab; TNF, tumor necrosis factor.
a
Factors including age, gender, RF, ACPA, Number of previous anti‐TNFα ≤1 and variables with P <
0.15 in univariate logistic regression are analyzed by multivariate logistic regression with back‐ ward
selection. Swollen joint count (SJC) and tender joint count (TJC) were excluded as they are
components of DAS28‐ESR.
*
P < 0.05.

unclear but might be related to a relatively small sample size, a differ‐
ent ethnicity and the baseline comorbidities. Also, the average age of our
patients (58.9 ± 10.6 years) was higher than those enrolled in the clinical
20
trials. Detection of RF increases as patients become older and are
exposed to accumulating kinds of microbes or environmental factors,
decreasing its accountability for RA. Further studies with longer
observation times, larger patient numbers, as well as prospec‐ tive data
collection in a real‐world situation would be necessary to demonstrate
their predictive usefulness. Similarly, several studies have suggested
that patients previously treated with no more than 1 anti‐TNFα have a
better response and are more likely to achieve low disease activity or
19,23
remission. In contrast, the present study did not show similar results.
Nevertheless, we adjusted this factor with a presence of RF and ACPA in
the multivariate logistic regression as they were recognized predictors.
RTX treatment appeared to be generally safe in our study. The
most frequent adverse events were infusion‐related, which were
relieved by lowering infusion rates and the administration of glu‐
cocorticoids and antihistamines. Only one serious infection event
happened by the end of the observation and there was no fatality.
Whether the infection was predisposed by interference of acquired
immunity resulting from long‐term administration of RTX is un‐
known and needs further studies. In the present investigation, we
have not found reactivation of latent tuberculosis infection (LTBI)
although some of the patients did have positive IGRA and under‐
went prophylactic therapy with isoniazid. Although RA patients have
24
a 2.7‐fold increase in the risk of developing TB, our findings are in
agreement with those reported previously in that there were no
25
increased risks of TB infection after RTX therapy. Since RTX has
no significant effect on release of interferon‐γ in RA patients with
LTBI, it is conceivable that RTX exerts it effect through a signal
transduction pathway other than Th1 inhibition or innate immune
8
suppression.
On the other hand, although our previous study has shown the
risk of reactivation of hepatitis B is significantly increased among
RTX‐treated RA patients (adjusted hazards ratio, 16.51; 95% CI
26
1.82‐149.67; P = 0.01) no reactivation of hepatitis B was docu‐
mented in the present investigation. This was largely because most
of our patients (43, 61.4%) had anti‐hepatitis B surface antibod‐ ies
(anti‐HBs) and a negligible HBV viral load at baseline and pos‐ sibly
also because the follow‐up period was not sufficiently long (24
months only).
8  | WANG
Although our present results are encouraging there are still
limitations in the investigation. These include its retrospective and
observational design, a relatively small sample size, and a possible
selection bias with a strong female preponderance in the RA cohort
from only a single referral center. Nevertheless, to our knowledge,
the present investigation is the 1st study in ethnic Asians, trying to
explore the real‐world data regarding the effectiveness and safety of
RTX in active RA patients who failed anti‐TNFα treatment. In ad‐
dition, it also provided detailed clinical information in a substantially
long time of observation, as well as a clear and segregated method‐
ology of evaluation on the effect of RTX in a complicated scenario of
tedious and variable combinations of csDMARDs.
5 | CONCLUSION
This real‐world study confirms the effectiveness and safety of RTX
in well‐documented active RA patients regardless of their prior anti‐
TNFα refractoriness. Our results also suggest patients may benefit
more from RTX if maintaining the concomitant MTX at a dosage of
more than 10 mg/wk.
AC K N OW L E D G E M E N T S
The authors would like to thank Dr. Yi‐Syuan Sun for his valuable
advice and assistance with the statistical analysis of this study. This
study was supported by the grants from the Ministry of Science &
Technology (MOST‐107‐2314‐B‐075 ‐051 ‐MY3) and Taipei
Veterans General Hospital (V107C‐084), Taiwan.
CONFLICTS OF INTEREST
The authors declare no conflicts of interest.
ORCID
Kai‐Chun Wang https://orcid.org/0000-0003-2037-6681
Hsien‐Tzung Liao https://orcid.org/0000-0001-5930-4840
Chien‐Chih Lai https://orcid.org/0000-0002-0546-8695
Ming‐Han Chen https://orcid.org/0000-0001-7822-2613
Chang‐Youh Tsai https://orcid.org/0000-0002-4154-4018
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