Research

JAMA Dermatology | Original Investigation

Safety and Efficacy of Methotrexate for Chinese

Adults With Psoriasis With and Without Psoriatic
Arthritis
Kexiang Yan, MD, PhD; Yuanjing Zhang, MD; Ling Han, MD, PhD; Qiong Huang, MD, PhD;
Zhenghua Zhang, MD, PhD; Xu Fang, MD; Zhizhong Zheng, MD, PhD; Nikhil Yawalkar, MD; Yuling
Chang, MD; Qun Zhang, MD; Ling Jin, MD; Danfeng Qian, MD; Xueying Li, MD; Mingshun Wu,
MD; Qiaohu Xu, MD; Xuejun Zhang, MD, PhD; Jinhua Xu, MD, PhD

IMPORTANCE It is necessary to determine whether psoriasis responds to methotrexate

in the same manner in patients with and without psoriatic arthritis.

OBJECTIVE To evaluate the effectiveness and safety of methotrexate in treating patients

with psoriasis with and without psoriatic arthritis.

DESIGN, SETTING, AND PARTICIPANTS In this prospective, single-arm, interventional study,

a total of 235 patients with psoriasis, 107 without psoriatic arthritis and 128 with
psoriatic arthritis who were receiving methotrexate therapy from April 1, 2015, to
December 31, 2017, were recruited from the outpatient department of a hospital at a
large Chinese university. There were no significant demographic or clinical differences
between the subgroups with the exception of diabetes.

INTERVENTIONS A 12-week course of low-dosage oral methotrexate (7.5-15 mg weekly).

MAIN OUTCOMES AND MEASURES Changes in disease severity, adverse events,

blood cell counts, and liver and renal function.

RESULTS A total of 235 patients with psoriasis (166 male [66.0%]; mean [SD] age, P
u
49.6 [15.1] years) received methotrexate treatment for 12 weeks. The 90% reduction
b
from baseline Psoriasis Area Severity Index response was significantly lower in patients l
with psoriatic arthritis than in patients without psoriatic arthritis at week 8 (4 0f 128 i
[3.1%] vs 12 of 107 s
h
[11.2%]; P = .02) and week 12 (19 of 128 [14.8%] vs 27 of 107 [25.2%]; P = .049). e
Furthermore, d
the incidence of adverse events, including dizziness (12 of 128 [9.4%] vs 1 of 107
[0.9%]; o
P = .007), gastrointestinal symptoms (32 of 128 [25.0%] vs 13 of 107 [12.1%]; P = . n
01), and l
i
hepatoxicity (34 of 128 [26.6%] vs 16 of 107 [15.0%]; P = .04), was significantly
n
higher in patients with psoriatic arthritis than in patients without psoriatic arthritis. e
Methotrexate- induced elevation of alanine aminotransferase levels was associated
with body mass index (mean [SD] body mass index, 26 [4] in patients with [P = . J
04] vs 26 [4] in those without a
[P = .005] psoriatic arthritis) and smoking (17 of 34 [50.0%] in patients with [P = .02] n
u
vs9 of 16 [56.3%] in those without [P = .04] psoriatic arthritis). a
r
CONCLUSIONS AND RELEVANCE In this study, methotrexate was well tolerated and y
effective in treating psoriasis. It was more effective, with fewer adverse effects, in
patients with psoriasis who did not have psoriatic arthritis than in patients who 3
0
presented with both psoriasis and psoriatic arthritis. Therefore, methotrexate can be ,
recommended as first-line treatment for psoriasis without arthritis.
2
0
1
9
.

JAMA Dermatol. doi:10.1001/jamadermatol.2018.5194

 Research
Hefei, Anhui, China
(Y. Zhang, Chang, Q. Zhang, Jin,
Qian, Li, Wu, Q. Xu); Department
of Dermatology, Inselspital, Bern
University Hospital, University of
Bern, Bern, Switzerland
(Yawalkar).
Corresponding Authors: Jinhua
Xu, MD, PhD (xjhhsyy@163.com),
and Xuejun Zhang, MD, PhD
(ayzxj@vip. sina.com), Shanghai
Institute of Dermatology,
Department of Dermatology,
Author Affiliations: Shanghai Institute of Dermatology, Department of Dermatology, Huashan Hospital,
Huashan Hospital, Fudan
Fudan University, Shanghai, China (Yan, Han, Huang,
Z. Zhang, Fang, Zheng, X. Zhang, University, No. 12 Middle
Wumunuqi Rd, Shanghai
J. Xu); Institute of Dermatology, Department of Dermatology, First Affiliated Hospital, Anhui Medical University,
200040, China.

E1
© 2019 American Medical Association. All rights reserved.
Downloaded from jamanetwork.com by Western Sydney University user on 01/31/2019
 Research Original Investigation Methotrexate for Chinese Adults With Psoriasis With and Without Psoriatic
Arthritis

P
soriasis is a chronic, immune-mediated more than 2-fold or less than 3-fold, the
inflammatory skin disease caused by the interaction methotrexate dose was reduced by 2.5 mg weekly
of multiple sus- ceptibility genes and environmental and ad- ministered once 2 to 4 weeks later. If the
factors that af- liver enzyme level el-
fects 1% to 3% of the population worldwide.1 The
prevalence of psoriasis in China is 0.47%.2 Systemic agents
available for psoriasis treatment include conventional
agents, such as ac- itretin, cyclosporine, and
methotrexate; targeted small- molecule drugs
(apremilast); and biologic agents that target distinct
proinflammatory cytokines. 3 Biologics and small-
molecule drugs are more expensive compared with
conven- tional drugs, which limits their widespread use,
especially in developing countries. Less than 10% of
patients with psoria- sis receive biologic agents routinely,
even in high-income countries.4
Methotrexate is a folate antagonist5 with anti-
6-9
inflamma- tory properties. Methotrexate has been used
as a first-line treatment for moderate to severe psoriasis
for more than 50 years.10 We undertook a prospective,
single-center, observa- tional study to assess the
effectiveness, tolerability, hematotox- icity, and
hepatotoxicity of oral methotrexate for the treatment of
patients with psoriasis without and with psoriatic arthritis.
To our knowledge, a prospective, comparative study of the
effi- cacy and adverse effects of methotrexate in Chinese
patients with psoriasis with and without psoriatic arthritis
has not yet been performed.

Methods
Study Population and Study Design
This single-center, prospective, single-arm, interventional
study was performed at the Department of Dermatology,
Huashan Hospital, Fudan University, Shanghai, China, from
April 1, 2015, to December 31, 2017. Patients 18 years or
older were recruited from the outpatient population.
Only patients with moderate to severe psoriasis with or
without psoriatic arthritis were included in this study.
Patients who received therapy with UV light, methotrexate,
or other sys- temic treatments for psoriasis or
arthropathy within 1 month of study initiation were
excluded. Topical treatments were stopped 1 week before the
start of the methotrexate treatment. The European
guidelines on contraindications and restrictions on
methotrexate use were followed. 11 The Medical Ethics
Committee of Huashan Hospital, Fudan Uni- versity,
reviewed and approved the protocol, and all patients
provided written informed consent. All data were
deidentified.

Treatment
The initial oral methotrexate dose was 7.5 to 10 mg once
weekly. The dose was increased by 2.5 mg every 2 to 4
weeks to a maxi- mum of 15 mg weekly depending on the
patient’s clinical re- sponse and adverse effects and results
of routine hematologic and blood chemistry tests. Folic acid
supplementation was not recommended because it is not
available in our clinics. If liver enzyme level elevations were

© 2019 American Medical Association. All rights

reserved.
Downloaded from jamanetwork.com by Western Sydney University user on 01/31/2019
 Research Original Investigation Methotrexate for Chinese Adults With Psoriasis With and Without Psoriatic
for the Study of Psoriatic Arthritis (CASPAR).13 Complete
Arthritis
Key Points blood cell counts, liver enzyme levels, and renal function
Question What are the differences in effectiveness and safety of methotrexate for measured
were patients with psoriasisand
at baseline with
atand without
weeks 4, 8, psoriatic
and 12. arthritis?
Findings In this Chinese cohort study of 107 patients with psoriasis without arthritis and 128 patients with psoriasis with psoriatic arthritis who were underg
Meaning Methotrexate may be more effective and may have fewer adverse effects in patients with psoriasis without concomitant psoriatic arthritis.
Statistical Analysis
The data are expressed as means (SDs). The statistical analy-
ses were performed using unpaired t tests, Mann-Whitney
tests, unpaired t tests with Welch correction, 1-way analyses
of variance with repeated measures, χ 2 tests, or Fisher exact
tests, as appropriate. Multiple test correction was conducted
using the Benjamini-Hochberg procedure. Data analyses
were performed using GraphPad Prism software, version 5
(GraphPad Software Inc). P < .05 was considered to be statis-
tically significant.

Results
Disease Duration and Likelihood of Having Diabetes
In total, 248 patients received oral methotrexate, and 235
pa- tients (166 male [66.0%]; mean [SD] age, 49.6 [15.1]
evations were more than 3-fold, methotrexate treatment was years) com- pleted the 12-week study. Five patients
stopped.12 dropped out at week 4, and 8 patients dropped out at week
8. No patient withdrew because of adverse effects. Four
Effectiveness and Tolerability Assessments patients had PASI scores greater than 50 when they
Two certified dermatologists graded the severity and extent of dropped out at week 8. The mean (SD) age at disease
psoriasis using the Psoriasis Area Severity Index (PASI) and body onset was 36.1 (16.1) years. The mean (SD) disease
surface area (BSA) scores and tabulated the adverse events. duration was 13.6 (11.1) years. The mean (SD) baseline
Psoriatic arthritis was assessed using the Classification Criteria PASI score was 13.9 (7.4), and the mean (SD) baseline BSA
score was 29.7 (20.8).

E2 JAMA Dermatology Published online January 30, 2019 jamadermatology.com

© 2019 American Medical Association. All rights

reserved.
Downloaded from jamanetwork.com by Western Sydney University user on 01/31/2019
 Methotrexate for Chinese Adults With Psoriasis With and Without Psoriatic Original Investigation Research
Arthritis

Table 1. Differences in Baseline Characteristics Between Patients With

Psoriasis With and Without Psoriatic Arthritisa
All Patients Patients With Psoriatic Patients Without Psoriatic
Characteristic (N = 235) Arthritis (n = 128) Arthritis (n = 107) P Valueb
Age, mean (SD), y 49.6 (15.1) 53.3 (12.0) 45.2 (17.1) <.001
Age at disease onset, 36.1 (16.1) 38.3 (15.9) 33.4 (16.1) .008
mean (SD), y
Disease duration, 13.6 (11.1) 15.0 (11.6) 11.8 (10.1) .02
mean (SD), y
Male 166 (70.6) 89.0 (69.5) 77.0 (72.0) .77
BMI 24.3 (3.4) 24.6 (3.2) 23.9 (3.5) .09 Abbreviations: BMI, body mass
index
(calculated as weight in
Baseline scores,
mean (SD) kilograms divided by height in
meters squared); BSA, body
PASI 13.9 (7.4) 14.3 (8.8) 13.5 (5.2) .58
surface area;
BSA 29.7 (20.9) 30.1 (23.6) 29.3 (17.1) .45 PASI, Psoriasis Area Severity Index.
Hypertension 90 (38.3) 56 (43.8) 34 (31.8) .08 a
Data are presented as
Diabetes 51 (21.7) 35 (27.3) 16 (15.0) .02 number (percentage) of
patients unless otherwise
Smoking 79 (33.6) 44 (34.4) 35 (32.7) .03
indicated.
Alcohol 54 (23.0) 35 (27.3) 19 (17.8) .09 b
Mann-Whitney test, unpaired t
Cumulative dose of 134 (21) 135 (23) 132 (18) .23 test, unpaired t test with
methotrexate, mean (SD), Welch correction, or Fisher exact
mg
test were used when
appropriate. P < .05 is
considered to be statistically
significant.

Table 2. Differential Efficacy of Methotrexate Treatment Between Patients With Psoriasis

With and Without Psoriatic Arthritis

proportions of patients who smoked and con-

Using the CASPAR criteria, 128 patients (54.5%) were

di- agnosed with psoriatic arthritis. Patients with psoriatic
arthri- tis had a longer duration of psoriasis before
entering the study. Furthermore, a significantly higher
proportion of patients with psoriatic arthritis had diabetes
compared with the 107 pa- tients without psoriatic arthritis.
The mean (SD) age (45.2 [17.1] vs 53.3 [12.0] years; P < .
001) and age at disease onset (33.2 [16.0] vs 38.3 [15.9]
years; P = .008) were significantly higher and the mean
(SD) disease duration (11.8 [10.1] vs
15.0 [11.6] years; P = .02) was significantly longer in
patients with psoriatic arthritis (Table 1). The number of
male pa- tients, body mass index (BMI) (calculated as
weight in kilo- grams divided by height in meters
squared), baseline PASI, BSA score, 50% reduction
from baseline PASI score (PASI50), 75% reduction
from baseline PASI score (PASI75), mean PASI changes at
weeks 8 and 12, incidence of hyper- tension, and
© 2019 American Medical Association. All rights
reserved.
Downloaded from jamanetwork.com by Western Sydney University user on 01/31/2019
 Outcome Arthritis (n = 128)Arthritis (n = 107)P Valuea
Outcomes at Week 8
Achievement, No. (%)
Methotrexate
PASI50 for Chinese Adults With
125 Psoriasis With
(53.2) and Without Psoriatic
61 (47.6) 64 (59.8) .07 Original Investigation Research
Arthritis
PASI75 57 (24.2) 29 (22.6) 28 (26.2) .54
PASI90 17 (7.2) 4 (3.1) 12 (1.9) .02
PASI change from Abbreviations:
baseline, 48.7BSA, body surface
(33.0) 45.8 (33.0) As(32.7)
52.1 indicated in Table
.12 2, the 90% reduction from baseline
mean (SD) area; PASI, Psoriasis Area Severity Index;
PASI score (PASI90) response rates were significantly
Outcomes at Week PASI50,
12 50% reduction from baseline PASI
score; PASI75, 75% reduction from higher in pa- tients without psoriatic arthritis compared
Achievement, No. (%)
baseline PASI score; PASI90, 90% with those with pso- riatic arthritis at week 8 (12 [1.9%] vs 4
PASI50 reduction from166 (70.6)
baseline PASI84score.
(65.6) 82 (76.6) .08
[3.1%]; P = .02) and week
PASI75 a
Mann-Whitney107 (45.5) 53exact
test and Fisher (41.4)
test 54 (50.5) .19
12 (27 [25.2%] vs 19 [14.8%]; P = .049). At week 8, the PASI50
PASI90 were used46 when appropriate.
(19.6) 19 (14.8) 27 (25.2)
P < .05 was considered to be response rates were.049 numerically higher, albeit not statisti-
Mean PASI change 62.2 (32.6) 60.1 (31.7) 64.8 (33.7)
from baseline, meanstatistically
(SD) significant. cally significant, in .10
the patients without psoriatic arthritis
com- pared with the patients with psoriatic arthritis (64
sumed alcohol did not differ between the patients with and [59.8%] vs 61 [47.6%]; P = .07), as were the PASI75
without psoriatic arthritis. response rates (28
[26.2%] vs 29 [22.6%]; P = .54) and the mean (SD) PASI changes
Effectiveness of Methotrexate in Patients (52.1 [32.7] vs 45.8 [33.0]; P = .12). At week 12, the PASI50 re-
With and Without Psoriatic Arthritis sponse rates were also numerically higher but not statisti-

jamadermatology.com JAMA Dermatology Published online January 30, 2019 E3

© 2019 American Medical Association. All rights

reserved.
Downloaded from jamanetwork.com by Western Sydney University user on 01/31/2019
 Research Original Investigation Methotrexate for Chinese Adults With Psoriasis With and Without Psoriatic
Arthritis

Table 3. Summary of Adverse Events

No. (%) of Patients

Patients Without
Patients With Psoriatic Psoriatic Arthritis
Adverse Event Total (N = 235) Arthritis (n = 128) (n = 107) P Valuea
Any adverse event 105 (44.7) 67 (52.3) 38 (35.5) .01
Reports of adverse effects 92 (39.1) 58 (45.3) 34 (31.8) .04
Fatigue 29 (12.3) 18 (14.1) 11 (10.3) .43
Dizziness 13 (5.5) 12 (9.4) 1 (0.4) .007
Headache 3 (1.3) 2 (1.6) 1 (0.9) >.99
Hair loss 3 (1.3) 3 (2.3) 0 .25
Total gastrointestinal tract 45 (19.1) 32 (25.0) 13 (12.1) .01
Nausea and vomiting 20 (8.5) 15 (11.7) 5 (4.6) .06
Dyspepsia 20 (8.5) 14 (10.9) 6 (5.6) .17
Abdominal pain 5 (2.1) 4 (3.1) 1 (0.9) .38
Diarrhea 8 (3.4) 6 (4.7) 2 (1.9) .31
Oral ulcers 3 (1.3) 0 3 (2.8) .09
Methotrexate-associated 61 (26.0) 38 (29.7) 21 (19.6) .10
abnormal hepatic function
ALT level
Elevation 50 (21.3) 34 (26.6) 16 (15.0) .04
>2 Times the ULN AST level 21 (8.9) 13 (10.2) 8 (7.5) .50

Elevation 29 (12.3) 19 (14.8) 10 (9.3) .24

>2 Times the ULN 3 (1.3) 1 (0.8) 2 (1.9) .59
DBIL elevation 11 (4.7) 6 (4.7) 5 (4.6) >.99
TBIL elevation 8 (3.4) 5 (3.9) 3 (2.8) .73
Methotrexate-associated 17 (7.2) 9 (7.0) 8 (6.5) >.99
cytopenia
Anemia 9 (3.8) 3 (2.3) 6 (5.6) .31
Abbreviations: ALT, alanine
Leukopenia 6 (3.8) 3 (2.3) 3 (2.8) >.99 transaminase; AST, aspartate
Neutropenia 4 (1.7) 2 (1.6) 2 (1.9) >.99 transaminase; DBIL, direct bilirubin;
NA, not applicable; TBIL, total
Thrombocytopenia 6 (2.6) 4 (3.1) 2 (1.9) .69 bilirubin; ULN, upper limit of
normal.
Serious adverse events 0 0 0 NA
Discontinuations attributable0 to adverse events 0
a
Fisher
0 exact test was used.NA
P < .05 is considered to be statistically
significant.

cally significant in the patients without psoriatic arthritis (AST) level (29 [12.3%]), elevated direct bilirubin level (11
com- pared with those with psoriatic arthritis (82 [76.6%] vs [4.7%]), and elevated total bilirubin level (8 [3.4%]).
84 [65.6%]; P = .08), as were the PASI75 response rates (54 Alanine aminotransferase levels more than 2 times the
[50.5%] up- per limit of normal were found in 21 patients (8.9%) and
vs 53 [41.4%]; P = .19) and the mean (SD) PASI changes (648 AST levels more than 2 times the upper limit of normal in 3
[33.7] vs 60.1 [31.7]; P = .10). pa- tients (1.3%). The percentage of elevated ALT levels in
pa- tients with psoriatic arthritis was significantly higher
Methotrexate Treatment–Associated Adverse Events than that in patients without psoriatic arthritis (34 [26.6%] vs
Table 3 summarizes the adverse events reported during 16 [15.0%]; P = .04). Cytopenia occurred in 17 patients
metho- trexate treatment, including all adverse effects (92 (7.2%), including anemia (9 [3.8%]), leukopenia (6
[39.1%]), methotrexate-associated abnormal hepatic [3.8%]), neutropenia (4
function (61 [26.0%]), and methotrexate-associated [1.7%]), and thrombocytopenia (6 [2.6%]). A significantly
cytopenia (17 [7.2%]). In total, 105 patients (44.7%) higher proportion of patients with psoriatic arthritis
reported having 1 or more ad- verse event. The most experienced diz- ziness (12 [9.4%] vs 1 [0.4%]; P = .007)
common reported adverse events were those of the and gastrointestinal
gastrointestinal tract (45 [19.1%]), including nau- sea and symptoms (32 [25.0%] vs 13 [12.1%]; P = .01) than those
vomiting (20 [8.5%]), dyspepsia (20 [8.5%]), ab- with- out psoriatic arthritis. The total number of adverse
dominal pain (5 [2.1%]), diarrhea (8 [3.4%]), and oral ulcer (3 events (67 [52.3%] vs 38 [35.5%]; P = .01) and reports of
[1.3%]), followed by fatigue (29 [12.3%]), dizziness (13 adverse effects
[5.6%]), (58 [45.3%] vs 34 [31.8%]; P = .04) in patients with
headache (3 [1.3%]), and hair loss (3 [1.3%]). Methotrexate- psoriatic arthritis were also significantly higher than in
associated liver enzyme level elevations occurred in 61 pa- patients with- out arthritis.
tients (26.0%), including elevated alanine aminotransferase Table 4 summarizes the association of methotrexate
(ALT) level (50 [21.3%]), elevated aspartate aminotransferase with hematologic variables and with liver and renal
© 2019 American Medical Association. All rights
reserved.
Downloaded from jamanetwork.com by Western Sydney University user on 01/31/2019
 Research Original Investigation Methotrexate for Chinese Adults With Psoriasis With and Without Psoriatic
Arthritis

function

E4 JAMA Dermatology Published online January 30, 2019 jamadermatology.com

© 2019 American Medical Association. All rights

reserved.
Downloaded from jamanetwork.com by Western Sydney University user on 01/31/2019
 Methotrexate for Chinese Adults With Psoriasis With and Without Psoriatic Original Investigation Research
Arthritis

Table 4. Association of Methotrexate With Routine Blood Test Results and Hepatic and Renal Function Analyses

Patients With Psoriatic Arthritis (n = 128) Patients Without Psoriatic Arthritis (n = 107)
Mean (SD) Mean (SD)
P
Variable Week 0 Week 8 Week 12 P Valuea Valuea
Week 0 Week 8 Week 12
RBC count, 4.87 (0.43) 4.72 (0.43) 4.67 (0.40) <.001 4.86 (0.47) 4.73 (0.47) 4.67 (0.48) <.001
×106/μL
MCV, μm3 90.58 (4.45) 91.77 (4.31) 92.42 (4.44) <.001 91.15 (4.05) 92.48 (4.21) 93.16 (3.94) <.001
Hemoglobin 14.66 (1.43) 14.44 (1.37) 14.41 (1.28) <.001 14.78 (1.38) 14.58 (1.32) 14.55 (1.42) .003
level, g/dL
WBC count, 6920 (1720) 1490 (1960) 6240 (1650) <.001 7060 (1950) 6560 (1990) 6610 (2070) .009
/μL
Neutrophil 4450 (1390) 4180 (1690) 4030 (1320) .005 4600 (1590) 4230 (1610) 4380 (1650) .054
count, /μL
Neutrophils, % 63.52 (8.27) 63.25 (8.26) 63.90 (7.97) .63 64.52 (6.94) 63.58 (6.97) 65.41 (7.12) .02
Lymphocytes, % 26.53 (7.79) 26.02 (7.44) 25.73 (7.43) .28 25.98 (6.32) 25.95 (6.03) 24.47 (5.99) .009
Monocytes, % 7.09 (1.73) 7.70 (2.11) 7.49 (1.96) <.001 6.79 (1.73) 7.57 (2.04) 7.41 (2.20) <.001
Platelet count, 233.00 (68.63) 232.40 (63.55) 231.00 (60.80) .86 232.10 (60.45) 235.90 (58.97) 232.90 (62.30) .51
×103/μL
ALT level, U/L 30.13 (17.49) 40.18 (35.56) 40.90 (36.70) <.001 32.32 (22.67) 36.16 (34.55) 35.76 (29.66) .41
AST level, U/L 22.51 (8.67) 25.46 (12.94) 25.84 (12.74)a .007 25.20 (19.22) 24.19 (11.98) 24.01 (10.18) .97
ALP level, U/L 83.55 (29.62) NA 83.15 (24.7) .78 80.67 (17.92) NA 80.79 (20.38) .91
γ-GGT level, 26.36 (19.2) NA 25.06 (19.21) .46 21.36 (18.21) NA 19.79 (11.01) .30
U/L
Albumin level, 4.56 (0.31) NA 4.62 (0.25) .02 4.66 (0.28) NA 4.66 (0.27) .73
g/dL
Globulin level, 3.04 (0.53) NA 2.96 (0.50) .014 2.92 (0.37) NA 2.95 (0.41) .47
g/dL
Albumin- 1.55 (0.30) NA 1.61 (0.29) .004 1.62 (0.23) NA 1.61 (0.26) .84
globulin ratio
DBIL, mg/dL 0.20 (0.10) NA 0.22 (0.09) .004 0.21 (0.09) NA 0.23 (0.09) .03
TBIL, mg/d 0.63 (0.34) NA 0.66 (0.27) .12 0.62 (0.24) NA 0.65 (0.24) .24
UA level, 0.01 (0.00) 0.01 (0.00) 0.36 (0.0) .99 0.36 (0.0) 0.36 (0.0) 0.36 (0.0) .52
mg/dL
CRE 0.76 (0.16) 0.76 (0.17) 0.75 (0.15) .24 0.77 (0.16) 0.76 (0.16) 0.76 (0.15) .87
concentration,
mg/dL
BUN 14.37 (3.53) 14.40 (3.61) 14.43 (3.42) .99 14.37 (3.81) 14.17 (3.73) 14.48 (3.73) .60
concentration,
mg/dL
Abbreviations: ALP, alkaline phosphatase; ALT, alanine multiply by 0.01; platelets to ×109/L, multiply by 1; ALT, AST, ALP, and γ-
transaminase; AST, aspartate transaminase; BUN, blood urea nitrogen; GGT to microkatals per liter, multiply by 0.0167; albumin and globulin to
CRE, creatinine; DBIL, direct bilirubin; HGB, hemoglobin; MCV, mean grams per liter, multiply by 10; DBIL and TBIL to micromoles per liter,
corpuscular volume; NA, not applicable; RBC, red blood cell; TBIL, multiply by 10; UA to micromoles per liter, multiply by 10; CRE to
total bilirubin; UA, uric acid; WBC, white blood cell; γ-GGT, γ- micromoles per liter, multiply by 88.4; and BUN to millimoles per liter,
glutamyltransferase. multiply by 0.357.
SI conversion factors: to convert RBCs to ×1012/L, multiply by 1; a
One-way analyses of variance with repeated measures and paired t tests
MCV to femtoliters, multiply by 1; hemoglobin to grams per liter, were used when appropriate. Multiple test correction was conducted
multiply by 10; WBCs to ×109/L, multiply by 0.001; neutrophils to using the Benjamini-Hochberg procedure. Results were compared
×109/L, multiply by 0.001; with baseline
percentages of neutrophils, lymphocytes, and monocytes to proportion of (0 weeks). P < .05 is considered to be statistically significant.
1.0,

indicators. Methotrexate was associated with a [P = .05] in patients without psoriatic arthritis),
significantly reduced mean (SD) red blood cell count and hemoglobin level (P < .001) and sig- nificantly
(from 4.87 [0.43] × 106/μL to 4.67 [0.40] × 106/μL in increased mean corpuscular volume (90.58 [4.45]
patients with pso- riatic arthritis [P < .001] and from 4.86
[0.47] × 106/μL to 4.67 [0.48]× 106/μL in patients without
psoriatic arthritis [P < .001]) (to convert to ×1012 per liter,
multiply by 1), white blood cell count (from 6920/μL
[1720/μL] to 6240/μL [1650/μL] [P < .001] in patients with
psoriatic arthritis and from 7060/μL [1950/ μL] to
6610/μL [2070/μL] [P = .009] in patients without pso-
riatic arthritis) (to convert to ×109 per liter, multiply by
0.001), neutrophil count (from 4450/μL [1390/μL] to
4030/μL [1320/ μL] [P = .005] in patients with psoriatic
arthritis and 4600/μL [1590/μL] to 4380/μL [1650/μL]
© 2019 American Medical Association. All rights
reserved.
Downloaded from jamanetwork.com by Western Sydney University user on 01/31/2019
 Methotrexate for Chinese Adults With Psoriasis With and Without Psoriatic Original Investigation Research
μm3 to 92.42 [4.44]
Arthritisμm3 [P < .001] in patients with psoriatic [0.09] mg/dL [P = .004] in patients with
arthritis and 91.15 [4.05] μm3 to 93.16 [3.94] μm3 [P < .001] in psoriatic arthritis and 0.21 [0.09] mg/dL to 0.23 [0.09]
patients without psoriatic arthritis) (to convert to ×109 per li- ter, mg/dL [P = .03] in patients without psoriatic arthritis) (to
multiply by 0.001), percentage of monocytes (7.09% [1.73%] to convert to micromoles per liter, multiply 10.0) from baseline
7.49% [1.96%] [P < .001] in patients with psoriatic to week 12. A significant increase in neutrophil count
arthritis and 6.79% [1.73%] to 7.41% [2.20%] [P < .001] in pa- tients (63.52% [8.27%] to 63.90 [7.97%] [P = .63] in patients with
without psoriatic arthritis) (to convert to proportion of 1.0, multiply psoriatic arthritis and 64.52% [6.94%] to 65.41% [7.12%] [P
by 0.01), and serum direct bilirubin level (0.20 [0.10] mg/dL to 0.22 = .02] in patients

jamadermatology.com JAMA Dermatology Published online January 30, 2019 E5

© 2019 American Medical Association. All rights

reserved.
Downloaded from jamanetwork.com by Western Sydney University user on 01/31/2019
 Research Original Investigation Methotrexate for Chinese Adults With Psoriasis With and Without Psoriatic
Arthritis

Table 5. Association of Alanine Transaminase Level as a Measure of Liver Function With Clinic Characteristics of Psoriasis a

Patients With Psoriatic Arthritis (n = 128) Patients Without Psoriatic Arthritis (n = 107)
Methotrexate-
Associated Elevated Level Methotrexate-
Elevated Level Elevated Before Associated
Normal Level Before Treatment Level Normal Level Treatment Elevated Level
Characteristic (n = 88) (n = 15) (n = 34) P Valueb (n = 81) (n = 15) (n = 16) P Valueb
Age, mean y 54 (12) 53 (9) 50 (11) .34 46 (18) 45 (15) 42 (15) .74
(SD),
Age at disease set, 39 (17) 37 (15) 37 (15) .85 34 (17) 30 (12) 32 (10) .54
on mean (SD),
Disease duration, 16 (11) 16 (13) 14 (13) .69 12 (10) 15 (12) 11 (9) .46
mean (SD), y
Male 59 (67) 11 (73) 25 (73) .74 55 (68) 12 (80) 14 (88) .25
BMI, mean 24 (3) 26 (4) 26 (4) .04 23 (3) 26 (4) 26 (4) .005
(SD)
Baseline scores,
mean (SD)
PASI 13 (8) 16 (12) 17 (10) .11 13 (5) 13 (4) 14 (5) .82
BSA 27 (21) 37 (31) 38 (27) .046 30 (16) 28 (19) 28 (22) .95
Smoking 25 (28.4) 7 (46.7) 17 (50.0) .02 23 (28.4) 5 (33.3) 9 (56.2) .04
Drinking 26 (29.5) 4 (26.7) 9 (26.5) .93 12 (14.8) 6 (40.0) 3 (18.8) .07
alcohol
Hypertension 38 (43.2) 10 (66.7) 14 (41.2) .21 23 (28.4) 8 (53.3) 5 (31.3) .16
Diabetes 24 (27.3) 3 (20.0) 11 (32.4) .66 13 (16.0) 2 (13.3) 2 (12.5) .92
Reports of adverse drug 43 (48.9) 7 (46.7) 11 (32.4) .25 27 (33.3) 4 (26.7) 4 (25.0) .74
reaction
Cumulative dose of 135 (22) 124 (29) 137 (22) .15 132 (18) 131 (22) 130 (13) .93
methotrexate,
mean (SD), mg
Score change 12 wk,
at mean (SD)
PASI 64 (27) 52 (33) 53 (38) .10 67 (32) 48 (40) 57 (41) .10
BSA 62 (39) 35 (53) 49 (41) .048 71 (34) 35 (56) 51 (55) .005
Abbreviations: BMI, body mass index (calculated as weight in kilograms b
One-way analyses of variance and χ2 test were used to compare
divided by height in meters squared); BSA, body surface area; PASI, elevation groups with normal group. Multiple test correction was
Psoriasis Area Severity Index. conducted using Benjamini-Hochberg procedure. P < .05 is
a
Data are presented as number (percentage) of patients unless considered to be statistically significant.
otherwise indicated.

without psoriatic arthritis) (to convert to proportion of 1.0, Fifteen patients with psoriatic arthritis (11.7%) and
mul- tiply by 0.01) and a decrease in lymphocyte count 15 patients without psoriatic arthritis (14.0%) had
(26.53% [7.79%] to 25.73% [7.43%] [P = .28] in patients with elevated ALT
psoriatic
arthritis and 25.98% [6.03%] vs 24.47% [5.99%] [P = .009])
(to convert to proportion of 1.0, multiply by 0.01) were
observed from baseline to week 12. The mean values of
serum ALT level (30.13 [17.49] U/L at baseline, 40.18 [35.56]
U/L at week 8, and
40.90 [36.70] at week 12; P < .001) and AST level (22.51
[8.67]
U/L at baseline, 25.46 [12.94] U/L, and 25.84 [12.74]
U/L; P = .007) were significantly increased in patients
with psori- atic arthritis compared with baseline (to
convert ALT and AST to microkatals per liter, multiply by
0.0167). Serum albumin levels (4.56 [0.31] g/dL to 4.62
[0.25] g/dL; P = .02) (to con- vert to grams per liter,
multiply by 10) and the albumin-to- globulin ratio (1.55
[0.30] to 1.61 [0.29]; P = .004) increased sig- nificantly,
and serum globulin levels (3.04 [0.53] g/dL to 2.96 [0.50]
g/dL; P = .01]) (to convert to grams per liter, multiply by
10) decreased significantly from baseline to week 12 in pa-
tients with psoriatic arthritis.

Association of Increased Liver Enzyme Levels in Patients

With Psoriasis With Smoking and BMI
© 2019 American Medical Association. All rights
reserved.
Downloaded from jamanetwork.com by Western Sydney University user on 01/31/2019
 Research Original Investigation Methotrexate for Chinese Adults With Psoriasis With and Without Psoriatic
levels before they received methotrexate. Consequently, the groups 2 and 3 patients with psoriatic arthritis were
Arthritis
patients were divided into 3 groups: group 1, patients whose ALT significantly higher than those in group 1 patients with
levels were normal before and after treatment; group 2, patients psoriatic arthritis (37 [31] and 38 [27] vs 27 [21]; P = .
whose ALT levels were elevated before methotrexate treatment; 046). The mean (SD) BSA changes in group 2 and 3
and group 3, patients who ex- perienced methotrexate- patients with psoriatic arthritis (35 [53] and 49 [41] vs 62
associated ALT level elevations. Methotrexate-associated [39]; P = .048) and patients without psoriatic arthritis (35
elevation of ALT level was associ- ated with body mass index [56] and 51 [55] vs 71 [34]; P = .005) were significantly
(mean [SD] body mass index, 26 lower than those in group 1 patients at week 12. Patients
[4] in the patients with psoriatic arthritis [P = .04] and 26 [4] in with psoriatic arthritis in group 2 received a lower mean
those without arthritis [P = .005]) and smoking (17 [50.0%] (SD) cumulative metho- trexate dose than those in group 1
in the patients with arthritis [P = .02] and 9 [56.2%] in those (124 [29] mg vs 135 [22] mg), but no statistically
without arthritis [P = .04]). The mean (SD) baseline BSA scores in significant differences were observed (P = .15) (Table
5).

E6 JAMA Dermatology Published online January 30, 2019 jamadermatology.com

© 2019 American Medical Association. All rights

reserved.
Downloaded from jamanetwork.com by Western Sydney University user on 01/31/2019
 Methotrexate for Chinese Adults With Psoriasis With and Without Psoriatic Original Investigation Research
Arthritis

smoking was observed between patients with vs without

Discussion psoriatic arthritis, but the mean BMI was higher in those
with vs without psoriatic arthritis, which might be one rea-
The effectiveness and safety of methotrexate therapy in son why methotrexate-induced liver enzyme elevations
pa- tients with and without psoriatic arthritis were were more frequent in patients with psoriatic arthritis. A
compared in a prospective, single-arm, interventional previous study 29 also reported that obesity and diabetes
study. Significantly more patients with psoriatic arthritis were significant risk factors for liver injury, which is
presented with diabe- tes at baseline. Similar findings consis- tent with our observation. However, the
have been reported by Coto- Segura et al,14 and increased mechanism of hepatotoxicity remains to be elucidated.
levels of adipokines that drive in- sulin resistance in Methotrexate-associated myelosuppression was similar
patients with psoriatic arthritis may provide an explanation in patients with and without psoriatic arthritis. The lack of
for this observation. 15 Our results demon- strated that use of concomitant folic acid might be related to the
50% of patients without and 41% of patients with psoriatic hematologic laboratory changes observed in this study.
arthritis achieved PASI75 responses after 12 weeks, which However, the rate of cytopenia (2.6%) was similar to
concurs with the findings reported by Boehncke and previously reported metho- trexate-related
Schön.16 Other investigators have reported that the PASI75 myelosuppression rates of 2% to 10.2%. 30,31 Mean
response rate can vary from 24% to 73% during 12 to 24 corpuscular volume elevations and hemoglobin level de-
weeks,17-24 depending on the methotrexate dose, the time creases have been ascribed to the inhibition of folic
when the response is measured, and the study’s design. metabo- lism during methotrexate therapy.32 The increase
Sta- tistical differences in PASI90 response at weeks 8 and in neutro- phils induced by methotrexate in patients
12 were observed between patients with and without without psoriatic arthritis might be associated with
psoriatic arthri- tis, which can be better explained by the infection. Monocyte levels in-
fact that psoriatic ar- thritis occurs later in psoriasis and a creased significantly after methotrexate treatment, but the
long-standing disease may be harder to control. 25 mechanism is unclear33; methotrexate has previously been
More patients with psoriatic arthritis reported dizziness re- ported to act as a strong differentiation factor for
and nausea or vomiting compared with patients without immature and undifferentiated monocytic cells in vitro.34
psoriatic arthritis. This difference might also be related Furthermore, metho- trexate treatment boosts systemic
to genetic factors.26 Sampaio-Barros et al27 described 8.8% monocyte generation.35 Ad- ditional studies are needed to
of patients with ankylosing spondylitis receiving identify the stimulatory factors involved in this process.
methotrexate treat- ment who reported dizziness, which is
consistent with 9.4% of patients with psoriatic arthritis in Limitations
our study who also expe- rienced dizziness. Overall, 105 The limitations of this study are its short intervention
patients (44.7%) reported methotrexate-associated course (12 weeks) and its single-center setting.
adverse events, which were mostly mild or moderate, and Gastrointestinal tract adverse events might have been
none of the patients dropped out of the study because of overestimated because no fo- lic acid supplementation was
severe adverse events. prescribed.
Methotrexate-associated abnormal hepatic function
was observed in 61 patients (26.0%), which was similar to
previ- ously reported incidence rates of 15% to 50%. 20
Moreover, abnormal hepatic function was more severe in
Conclusions
patients with psoriatic arthritis than in those without Our study demonstrated that methotrexate was well toler-
psoriatic arthritis. Smoking and increased BMI are ated by Chinese outpatients with psoriasis. Methotrexate
important risk factors in patients with psoriasis with ALT ap- peared to be more effective and had fewer adverse
level elevations. Associated with significantly lower effects in patients without psoriatic arthritis compared
methotrexate polyglutamate 3 con- centrations in red with those with psoriatic arthritis. Although multicenter
blood cells, smoking increases the basal metabolic rate in trials with larger sample size are needed to confirm these
patients with rheumatoid arthritis and may affect drug results, our findings suggest that methotrexate can be
metabolism.28 No difference in the percentage of recommended as first-line treatment for psoriasis without
arthritis.

ARTICLE INFORMATION Concept and design: Yan,

Drafting of the manuscript: Yan, Y. Zhang, Han,
Fang, Zheng, X. Zhang, J.
Accepted for Publication: November 15, Z. Zhang.
Xu.
2018. Critical revision of the manuscript for important
Acquisition, analysis, or
Published Online: January 30, 2019. interpretation of data: Yan, intellectual content: Yan, Y. Zhang, Huang, Fang, Zheng,
doi:10.1001/jamadermatol.2018.5194 Y. Zhang, Han, Huang, Z. Yawalkar, Chang, Q. Zhang, Jin, Qian, Li, Wu,
Zhang, Yawalkar, Chang, Q. Q. Xu, X. Zhang, J. Xu.
Author Contributions: Drs Yan and Y.
Zhang, Jin, Qian, Li, Wu, Statistical analysis: Yan, Y. Zhang, Fang.
Zhang contributed equally to this article.
Q. Xu. Obtained funding: Yan, Fang, Zheng, X. Zhang.
Drs Yan and
Administrative, technical, or material support: Yan,
Y. Zhang had full access to all the data in the
Y. Zhang, Han, Huang, Z. Zhang, Fang, Zheng, Chang,
study and take responsibility for the integrity
Q. Zhang, Jin, Qian, Li, Wu, Q. Xu, J. Xu. Supervision:
of the data and the accuracy of the data
Yan, Zheng, Yawalkar, X. Zhang, J. Xu.
analysis.
© 2019 American Medical Association. All rights
reserved.
Downloaded from jamanetwork.com by Western Sydney University user on 01/31/2019
 Methotrexate for Chinese Adults With Psoriasis With and Without Psoriatic Original Investigation Research
Conflict of Interest Disclosures:
Arthritis None reported. analysis, and interpretation of the data;
Funding/Support: This research was
preparation, review, or approval of the
supported by grant 81773322 from
manuscript; and decision to submit the
the National Natural Science
manuscript for publication.
Foundation of China.
Additional Contributions: Weilin Pu, PhD,
Role of the Funder/Sponsor: The
State Key Laboratory of Genetic
funding source had no role in the
Engineering, Collaborative Innovation
design and conduct of the study;
Center for Genetics and Development,
collection, management,
School of Life Sciences, Fudan

jamadermatology.com JAMA Dermatology Published online January 30, 2019 E7

© 2019 American Medical Association. All rights

reserved.
Downloaded from jamanetwork.com by Western Sydney University user on 01/31/2019
 Research Original Investigation Methotrexate for Chinese Adults With Psoriasis With and Without Psoriatic
Arthritis

University, Shanghai, China, provided guidance

in statistics, and Yang Zhao, PhD, Shanghai 13. Taylor W, Gladman D, Helliwell P, (hydroxyurea) as a weekly dose to treat
International Studies University, Shanghai, Marchesoni A, Mease P, Mielants H; CASPAR moderate-to-severe chronic plaque psoriasis:
China, provided guidance in language. They Study Group. Classification criteria for a comparative study. J Dermatolog Treat.
were not compensated for their help. psoriatic arthritis: development of new 2007;18 (5):295-300.
criteria from a large international study. doi:10.1080/09546630701499291
REFERENCES Arthritis Rheum. 2006;54(8): 2665-2673. 25. Kerschbaumer A, Fenzl KH, Erlacher L, Aletaha
doi:10.1002/art.21972 D. An overview of psoriatic arthritis:
1. Nestle FO, Kaplan DH, Barker J.
Psoriasis. N Engl J Med. 2009;361(5):496-509. 14. Coto-Segura P, Eiris-Salvado N, González- epidemiology, clinical features,
doi:10.1056/ NEJMra0804595 Lara L, et al. Psoriasis, psoriatic arthritis and pathophysiology and novel treatment targets.
type 2 diabetes mellitus: a systematic review Wien Klin Wochenschr. 2016;128 (21-22):791-795.
2. Ding X, Wang T, Shen Y, et al. and doi:10.1007/s00508-016-1111-9
Prevalence of psoriasis in China: a meta-analysis. Br J Dermatol. 2013;169(4):783-793.
population-based study in six cities. Eur J 26.Swale VJ, Sahota A. Severe vertigo
doi:10.1111/bjd.12473 requiring hospitalization whilst taking low-
Dermatol. 2012;22(5):663-667.
15. Eder L, Jayakar J, Pollock R, et al. dose oral methotrexate for psoriasis. Clin
3. Rizvi S, Chaudhari K, Syed BA. The Serum adipokines in patients with psoriatic Exp Dermatol. 2005;30(3):295-296.
psoriasis drugs market. Nat Rev Drug Discov. arthritis and psoriasis alone and their doi:10.1111/j.1365-2230.2005. 01742.x
2015;14(11): 745-746. correlation with disease activity. Ann Rheum Dis.
doi:10.1038/nrd4763 27. Sampaio-Barros PD, Costallat LT,
2013;72(12):1956-1961. Bertolo MB, Neto JF, Samara AM. Methotrexate
4. Lebwohl MG, Kavanaugh A, Armstrong doi:10.1136/annrheumdis-2012-202325 in the treatment of ankylosing spondylitis.
AW, Van Voorhees AS. US perspectives 16. Boehncke WH, Schön MP. Psoriasis. Lancet. Scand J Rheumatol. 2000;29(3):160-162.
in the management of psoriasis and psoriatic 2015; 386(9997):983-994. doi:10.1016/S0140- doi:10.1080/ 030097400750002021
arthritis: patient and physician results 6736(14) 61909-7
from the population-based Multinational 28.Stamp LK, O’Donnell JL, Chapman PT, et
Assessment of 17. Barker J, Hoffmann M, Wozel G, et al. al. Determinants of red blood cell
Psoriasis and Psoriatic Arthritis (MAPP) survey. Efficacy and safety of infliximab vs. methotrexate polyglutamate concentrations
Am J Clin Dermatol. 2016;17(1):87-97. methotrexate in patients with moderate-to- in rheumatoid arthritis patients receiving long-
doi:10.1007/ s40257-015-0169-x severe plaque psoriasis: results of an open-label, term methotrexate treatment. Arthritis Rheum.
active-controlled, randomized trial 2009;60(8):2248-2256.
5. Cipriani P, Ruscitti P, Carubbi F, Liakouli V, (RESTORE1). Br J Dermatol. 2011; 165(5):1109- doi:10.1002/art.24653
Giacomelli R. Methotrexate: an old new drug 1117. doi:10.1111/j.1365-2133.2011.10615.x
in autoimmune disease. Expert Rev Clin 29.Berends MA, Snoek J, de Jong EM, et al.
Immunol. 2014;10(11):1519-1530. 18. Saurat JH, Stingl G, Dubertret L, et Liver injury in long-term methotrexate
doi:10.1586/1744666X.2014. 962996 al; CHAMPION Study Investigators. Efficacy and treatment in psoriasis is relatively infrequent.
safety results from the randomized controlled Aliment Pharmacol Ther. 2006;24(5):805-811.
6. Elango T, Dayalan H, Subramanian S, comparative study of adalimumab vs. doi:10.1111/j.1365-2036. 2006.03047.x
Gnanaraj P, Malligarjunan H. Serum methotrexate vs. placebo in patients with
interleukin-6 levels in response to 30.Ohosone Y, Okano Y, Kameda H, et al.
psoriasis (CHAMPION). Br J Dermatol. Toxicity of low-dose methotrexate in rheumatoid
methotrexate treatment in psoriatic patients. 2008;158(3):558-566. doi:10.1111/j. 1365-
Clin Chim Acta. 2012;413(19-20):1652-1656. arthritis: clinical characteristics in patients with
2133.2007.08315.x MTX-induced pancytopenia and interstitial
doi:10.1016/j.cca.2012.05.007
19. Akhyani M, Chams-Davatchi C, Hemami pneumonitis [in Japanese]. Ryumachi.
7. Kuhn A, Ruland V, Patsinakidis N, Luger TA. MR, Fateh S. Efficacy and safety of 1997;37(1):16-23. Rheumatism.
Use of methotrexate in patients with psoriasis. mycophenolate mofetil vs. methotrexate for
Clin Exp Rheumatol. 2010;28(5)(suppl 61):S138- 31. Kinder AJ, Hassell AB, Brand J,
the treatment of chronic plaque psoriasis. J Brownfield A, Grove M, Shadforth MF. The
S144. Eur Acad Dermatol Venereol. 2010;24(12):1447- treatment of inflammatory arthritis with
8. Olsen NJ, Spurlock CF III, Aune TM. 1451. doi:10.1111/j.1468- 3083.2010.03667.x methotrexate in clinical practice: treatment
Methotrexate induces production of IL-1 and IL- duration and incidence of adverse drug
20.Dogra S, Krishna V, Kanwar AJ. Efficacy
6 in the monocytic cell line U937. Arthritis Res reactions. Rheumatology (Oxford). 2005;44(1):61-
and safety of systemic methotrexate in two
Ther. 2014;16(1):R17. doi:10.1186/ar4444 fixed doses of 10 mg or 25 mg orally once 66. doi:10.1093/rheumatology/keh512
9. Tamilselvi E, Haripriya D, Hemamalini M, weekly in adult patients with severe 32. Chan ES, Cronstein BN. Molecular
Pushpa G, Swapna S. Association of disease plaque-type psoriasis: action of methotrexate in inflammatory diseases.
severity with a prospective, randomized, double-blind, Arthritis Res. 2002;4(4):266-273.
IL-1 levels in methotrexate-treated psoriasis dose-ranging study. Clin Exp Dermatol. 2012;37(7): doi:10.1186/ar419
patients. Scand J Immunol. 2013;78(6):545-553. 729-734. doi:10.1111/j.1365-2230.2012.04440.x
doi:10.1111/sji.12117 33. Boehm I, Wenzel J. FACS
21. Fallah Arani S, Neumann H, Hop WC, monitoring of lymphocyte-subsets in patients
10. Yélamos O, Puig L. Systemic Thio HB. Fumarates vs. methotrexate in with discoid and subacute-cutaneous lupus
methotrexate for the treatment of psoriasis. moderate to severe chronic plaque psoriasis: a erythematosus receiving low-dose methotrexate.
Expert Rev Clin Immunol. 2015;11(5):553-563. multicentre prospective randomized controlled Scand J Rheumatol. 2002; 31(4):216-220.
doi:10.1586/1744666X.2015. 1026894 clinical trial. Br J Dermatol. 2011;164(4):855-861. doi:10.1080/030097402320318404
11. Nast A, Jacobs A, Rosumeck S, doi:10.1111/j.1365-2133.2010. 10195.x
34.Seitz M, Loetscher P, Dewald B, et al.
Werner RN. Methods report: European S3- 22. Flytström I, Stenberg B, Svensson A, Methotrexate action in rheumatoid
Guidelines on the systemic treatment of Bergbrant IM. Methotrexate vs. ciclosporin in arthritis: stimulation of cytokine inhibitor and
psoriasis vulgaris: update 2015: EDF in psoriasis: effectiveness, quality of life and inhibition of chemokine production by
cooperation with EADV and IPC. J Eur Acad safety: peripheral blood mononuclear cells. Br J
Dermatol Venereol. 2015;29(12):e1-e22. doi: a randomized controlled trial. Br J Dermatol. Rheumatol. 1995;34(7): 602-609.
10.1111/jdv.13353 2008; 158(1):116-121. doi:10.1093/rheumatology/34.7.602
12. Raaby L, Zachariae C, 23. Heydendael VM, Spuls PI, Opmeer 35. Taylor A, Sheng KC, Herrero LJ, Chen
Østensen M, et al. Methotrexate use and BC, et al.
W, Rulli NE, Mahalingam S. Methotrexate
monitoring in patients with psoriasis: a Methotrexate versus cyclosporine in
treatment causes early onset of disease in a
consensus report based on a Danish Expert moderate-to-severe chronic plaque psoriasis.
mouse model of Ross River virus–induced
Meeting. Acta Derm Venereol. 2017;97(4): 426- N Engl J Med. 2003;349(7):658-665.
inflammatory disease through increased
432. doi:10.2340/00015555-2599 doi:10.1056/ NEJMoa021359 monocyte production. PLoS One. 2013;8
24.Ranjan N, Sharma NL, Shanker V, Mahajan (8):e71146. doi:10.1371/journal.pone.0071146
VK, Tegta GR. Methotrexate versus
hydroxycarbamide

© 2019 American Medical Association. All rights

reserved.
Downloaded from jamanetwork.com by Western Sydney University user on 01/31/2019
 Research Original Investigation Methotrexate for Chinese Adults With Psoriasis With and Without Psoriatic
Arthritis

E8 JAMA Dermatology Published online January 30, 2019 jamadermatology.com

© 2019 American Medical Association. All rights

reserved.
Downloaded from jamanetwork.com by Western Sydney University user on 01/31/2019