Rheumatology 2019;58:131–134

RHEUMATOLOGY doi:10.1093/rheumatology/key275
Advance Access publication 4 September 2018

Concise report
The effects of methotrexate and hydroxychloroquine
combination therapy vs methotrexate monotherapy
in early rheumatoid arthritis patients

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Lisa Schapink1,2, Cornelia H. M. van den Ende1,2, Laura A. H. A. Gevers2,
Annelies E. van Ede2 and Alfons A. den Broeder1,2

Abstract
Objectives. To investigate the added value of MTX-HCQ combination therapy (CTG) in early RA in a controlled cohort
study. MTX monotherapy (MTG) is recommended as (part of) first choice treatment but no head-to-head comparisons are
available comparing MTX–HCQ CTG with MTG.
Methods. RA patients from the Sint Maartenskliniek and Radboudumc Nijmegen who started MTX with or without
concomitant HCQ from April 2010 to October 2015 were included. The primary outcome was the between-group

DAS28-CRP at 6 months, and secondary outcomes were
DAS28-CRP at 12 months, EULAR response at 6 and
12 months, and treatment intensification. Regression modelling was used to correct for confounding.
Results. We included 325 patients, with only small between-group differences at baseline. The DAS28-CRP improve-
ment at 6 months was larger in the CTG (
= 0.38 (CI: 0.01, 0.76)), and the difference between groups in DAS28-CRP
improvement was smaller at 12 months (
= 0.22 points (CI: 0.19, 0.62)). At 6 months, a higher percentage of patients
had a good EULAR response in the CTG (
= 15% (CI: 2.7%, 27%)). This difference was reduced at 12 months (
= 6%
(CI 6.4%, 19%)). Treatment intensification with conventional synthetic DMARDs was more likely in the MTG (
= 31%
(CI: 43%, 19%)). The proportion of patients starting biologic DMARD treatment during the observation period was
comparable (
= 2% (CI: 8%, 12%)).
Discussion. In contrast to indirect comparison review data, MTX–HCQ seems somewhat more effective after 6 months
than MTX monotherapy in early RA patients. After 12 months, we observed no significant differences between the two
strategies, probably due to treat-to-target efforts.

CLINICAL
SCIENCE
Key words: RA, DMARDs, Methotrexate, Hydroxychloroquine, clinical trials

Rheumatology key messages

. Methotrexate–hydroxychloroquine combination therapy may cause lower disease activity in early RA than
methotrexate monotherapy.
. Methotrexate monotherapy as first early RA treatment seems to lead to more treatment intensification.

Introduction MTX can be given as monotherapy or in combination

with other conventional synthetic DMARDs (csDMARDs).
Reaching remission in early RA is crucial for ameliorating Several recent studies, including a meta-analysis, how-
current complaints and preventing future functional loss ever, show that most MTX-based csDMARD combination
[1–3]. MTX is recommended as (part of) the first treatment treatments are no more effective than MTX monotherapy,
in early RA by the EULAR and the ACR due to its favour- with the exception of MTX–SSZ–HCQ and possibly
able balance in effectiveness, safety profile and costs MTX–LEF [8–10].
[4–7] . An interesting csDMARD combination that is often
used is MTX–HCQ. At our clinics in Nijmegen (Sint
Maartenskliniek and Radboudumc), MTX–HCQ combin-
1
Department of Rheumatology, Sint Maartenskliniek and 2Department ation therapy—together with a DAS28-based treat-to-
of Rheumatology, Radboudumc, Nijmegen, the Netherlands
target treatment strategy—has been part of the early RA
Submitted 4 April 2018; revised version accepted 17 July 2018
treatment protocol since 2010, for several reasons. Firstly,
Correspondence to: Lisa Schapink, Department of Rheumatology, Sint at that time the ACR guideline advocated the use of this
Maartenskliniek, PO Box 9011, 6500 GM, Nijmegen, the Netherlands.
E-mail: L.schapink@maartenskliniek.nl combination [11]; secondly, triple therapy was considered

! The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com
Lisa Schapink et al.
to be less practical and acceptable for both patient and
physician and thirdly, biologic DMARD (bDMARD) treat-
ment was only reimbursed after failure of at least two
csDMARDs in the Netherlands [12]. However, head-to-
head trials comparing MTC-HCQ combination therapy
with MTX monotherapy are still absent, and indirect com-
parison meta-analyses suggest that the combination is
not superior over MTX alone [10].
As both MTX monotherapy and MTX–HCQ combination
therapy have been used frequently for early RA patients in
our hospitals, we had the opportunity to carry out a con-
trolled, quasi-experimental study design comparing the
effectiveness of MTX–HCQ combination treatment with
MTX monotherapy.
Methods
In this prospective observational early RA cohort study,
MTX monotherapy vs MTX–HCQ combination therapy
were compared for 1 year.
Patients
Data from RA patients starting MTX as first DMARD be-
tween April 2010 and October 2015 that had been pro-
spectively collected in the specialized hospital Sint
Maartenskliniek and academic hospital Radboudumc
(both located in Nijmegen, the Netherlands) were used.
From these cohorts, all consenting adult (518 years) RA
patients (ACR/EULAR 2010 criteria and/or diagnosis by a
rheumatologist) who started either MTX or MTX–HCQ
combination therapy as first DMARD treatment were
included in the present study. Patients with more than
one missing 3-monthly disease activity assessment or
had follow-up less than 1 year were excluded. The use
of patients’ data at both clinics was approved by the
local human research commission and registered under
CMO 2009/079 and CMO 2011/299.
Treatments
Included patients were grouped by initial treatment strat-
egy. Patients that started HCQ between 4 weeks before
and 4 weeks after the start of MTX were included in the
combination therapy group, other patients in the MTX
monotherapy group. Protocolled treatment of RA patients
at both clinics consisted of: MTX 25 mg/week (reaching
maximum dose within 4–8 weeks), preferably subcutane-
ously, and HCQ 400 mg/day as soon as feasible after
diagnosis. Folic acid 10 mg/week is standard-prescribed
to minimize MTX side effects. At start of treatment, pa-
tients are offered corticosteroid treatment, either intra-
muscular methylprednisolone injection (120 mg) or
tapered oral prednisolone. All treatment decisions were
left to the discretion of the health care provider.
Outcomes
Disease activity (DAS28-CRP) scores and components
(swollen joint count, tender joint count, visual analogue
scale patient global health and CRP) were collected
from baseline, 6-month and 12-month visits. For missing
132
DAS28-CRPs, the score was calculated with the compo-
nents available.
Primary outcome is the
DAS28-CRP between base-
line and 6 months. Secondary outcomes include
DAS28-
CRP between baseline and 12 months, the proportion with
good, moderate and/or no EULAR response at 6 and
12 months, and the proportion of patients who started
an extra csDMARD or any bDMARD treatment.
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Data and statistical analysis
Age, gender, RF, CCP antibody (anti-CCP) results, dur-
ation of symptoms, the 2010 ACR criteria, mean dosages
of MTX and HCQ and the number of injections given intra-
articular and intramuscular were collected to allow
baseline comparison. An intention-to-treat analysis was
conducted. Data were analysed using an unpaired t test,
2 test and a Wilcoxon rank-sum test on the continuous,
dichotomous and non-parametrically distributed vari-
ables, respectively. To correct as much as possible for
confounding by indication, linear regression was used
for primary outcome analyses. Potential confounders
that were included in the model were age and sex, pro-
portion of patients meeting the ACR 2010 criteria, RF
positivity (anti-CCP was excluded in the regression
model because of multicollinearity), mean dose over the
first 6 months and administration route of MTX, and the
use of intra-articular steroids, intramuscular steroids and
oral prednisolone. SPSS Statistics version 23 (IBM Corp.,
Armonk, NY, USA) was used for the analyses.
Results
Baseline characteristics
Two hundred and forty-six combination therapy patients
were compared with 79 monotherapy patients. Patients
who started combination therapy generally had a less fa-
vourable prognosis with regard to RA outcomes, with
higher prevalence of RF and anti-CCP and ACR 2010 cri-
teria, and received MTX more often subcutaneously with a
higher dose (Table 1).
Disease activity and EULAR response
The crude between-group difference in
DAS28-CRP at
6 months differed significantly, 0.46 points (CI: 0.10, 0.81),
with corrected difference of 0.38 points (CI: 0.010, 0.76).
At 12 months, the crude and corrected
DAS28-CRP
were no longer significantly different, 0.33 points (CI:
0.05, 0.71), with corrected difference of 0.22 points
(CI: 0.19, 0.62). The percentage of patients with a
good EULAR response differed significant at 6 months
with 61% vs 46% in the combination therapy and the
monotherapy group, respectively (
= 15% (CI: 2.7%,
27%)). At 12 months, this difference was reduced to
66% vs 60% in the combination therapy group and mono-
therapy group, respectively (
= 6% (CI 6.4%, 19%))
(Table 2).
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 The effects of MTX and HCQ

TABLE 1 Baseline characteristics

Monotherapy Combination therapy CI from the

(n = 79) (n = 246) Difference difference

DAS28-CRP baseline, mean (S.D.) 4.0 (1.2) 4.0 (1.1) 0 0.27, 0.33
Age, mean (S.D.), years 62 (14) 59 (14) 3 6.1, 1.6
Women, n (%) 52 (66) 152 (62) (4%) 8%, 15%
RF positive, n (%) 37 (47) 167 (68) (21%) 8.6%, 33%

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Anti-CCP positive, n (%) 36 (47) 166 (68) (22%) 9.4%, 34%
ACR/EULAR 2010 criteria, n (%) 67 (85) 228 (93) (8%) 0.5%, 18%
Radboudumc, n (%) 25 (32) 55 (22) (10%) 0.1%, 21%
Oral prednisone, n (%) 20 (25) 63 (26) (1%) 11%, 10%
MTX taken s.c., n (%) 43 (54) 169 (69) (15%) 2%, 27%
Dosage MTX, mean (S.D.), mg/week 19 (3.9) 21 (3.3) 2 0.82, 2.9
i.a. steroid injection, n (%) 12 (15) 25 (10) (5%) 2.6%, 15%
i.m. steroid injection, n (%) 42 (53) 120 (49) (4%) 8.1%, 17%

i.a.: intra-articular; i.m.: intramuscular; s.c.: subcutaneous.

TABLE 2 Primary and secondary outcomes

Combination CI from the

therapy Monotherapy Adjusted (adjusted)
(n = 246) (n = 79) Difference difference difference

DAS28-CRP 6 months, mean (S.D.) 2.3 (1.0) 2.8 (1.2) 0.5 0.82, 0.20

DAS28-CRP 6 months, mean (S.D.) 1.7 (1.3) 1.2 (1.6) 0.5 0.38 0.76, 0.010
DAS28-CRP 12 months, mean (S.D.) 2.1 (1.0) 2.4 (1.1) 0.3 0.6, 0.01

DAS28-CRP 12 months, mean (S.D.) 1.8 (1.4) 1.5 (1.6) 0.3 0.22 0.19, 0.62
Patients started bDMARD treatment, n (%) 46 (19) 13 (17) (2%) 8%, 12%
Patients started extra csDMARD, n (%) 27 (11) 33 (42) ( 31%) 43, 19
EULAR response 6 months, n (%)
Good 149 (61) 36 (46) (15%) 2.7%, 27%
Moderate/no response 96 (39) 43 (54) ( 15%)
EULAR response 12 months, n (%)
Good 143 (66) 44 (60) (6%) 6.4%, 19%
Moderate/no response 73 (34) 29 (40) ( 6%)

Treatment adjustment as found by Carmichael et al. [13]. The effect found of

Prescription of an extra csDMARD (HCQ (>4 weeks after
the start of MTX), LEF or SSZ was more likely in the mono-
therapy group (41%) than in the combination therapy
group (18%) (
= 31% (CI: 43%, 19%)). The cumulative
incidence of bDMARD treatment was comparable be-
tween the groups: monotherapy (17%) and the combin-
ation therapy (19%) (
= 2% (CI: 8%, 12%)) (Table 2).
Discussion
To our knowledge, this study is the first directly comparing
MTX monotherapy vs MTX–HCQ combination therapy in
early RA and showing that indeed treatment with
MTX–HCQ combination therapy results in a statistically
significant larger decrease of DAS28-CRP after 6 months
than MTX monotherapy.
An explanation for the effect of combination therapy
could be the fact that HCQ increases exposure to MTX
combination MTX-HCQ also seems valid when taking
into account that the combination MTX-SSZ has been
shown not to be better than MTX monotherapy, but that
the MTX-SSZ-HCQ combination indeed outperforms MTX
monotherapy [14]. This might suggest that it is the HCQ
component of the triple therapy rather than the SSZ com-
ponent that makes the difference. This is also corrobo-
rated by the fact that MTX and SSZ are both folic acid
antagonist, and that response to SSZ is very rare after
failure to MTX [15].
This study has its limitations. Firstly, the study is not a
randomized trial and results are thus susceptible to con-
founding. However, we corrected with linear regression
for measured confounders. Also, combination treatment
was preferentially given to patients with worse RA, so
this would result in bias in the conservative direction.
Secondly, intention-to-treat analysis was conducted,
whereas to be able to estimate true treatment effects, a

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Lisa Schapink et al.
per protocol analysis would be preferable. However, the
intention-to-treat approach has two advantages. It allows
us to infer whether a treatment strategy of starting with
combination therapy is superior to staring with MTX
monotherapy, and also an intention-to-treat analysis is
again the more conservative method for assessing super-
iority. This is reflected in the disappearance of the out-
come differences at 12 months, which is probably due to
treatment intensification in the monotherapy group; 42%
started an extra csDMARD, compared with 11% in the
combination therapy group (p = 0.00) as a sign of good
treat-to-target efforts.
Finally, we did not collect data about adverse events.
Although only the combination therapy group started with
HCQ, we do not expect a big difference in adverse events
between the monotherapy and combination therapy
group, since HCQ is generally seen as a relatively non-
toxic agent, as stated by Fries et al. [16].
Our findings seem to somewhat contradict the system-
atic review by Hazlewood et al. The review stated that
there is indirect evidence for the effectiveness of adding
HCQ to MTX treatment when patients fail on MTX mono-
therapy, but that there was no difference found between
MTX and MTX combination therapy as first treatment in
RA [10]. However, the comparison Hazlewood et al. made
was indirect, a method still under discussion. Also avail-
able data were limited.
In conclusion, in early RA, MTX–HCQ combination leads
to a larger decrease of DAS28-CRP after 6 months than
MTX monotherapy. Although this study showed only a
modest gain in disease control, this combination could
be an attractive option, in part because HCQ has low
risk for side effect and low costs.
Funding: No specific funding was received from any
bodies in the public, commercial or not-for-profit sectors
to carry out the work described in this manuscript.
Disclosure statement: The authors have declared no
conflicts of interest.
References
1 Kyburz D, Gabay C, Michel BA, Finckh A. The long-term
impact of early treatment of rheumatoid arthritis on
radiographic progression: a population-based cohort
study. Rheumatology (Oxford) 2011;50:1106–10.
2 Van Aken J, Lard LR, le Cessie S et al. Radiological out-
come after four years of early versus delayed treatment
strategy in patients with recent onset rheumatoid arthritis.
Ann Rheum Dis 2004;63:274–9.
3 Nell VPK, Machold KP, Eberl G et al. Benefit of very early
referral and very early therapy with disease-modifying
anti-rheumatic drugs in patients with early rheumatoid
arthritis. Rheumatology (Oxford) 2004;43:906–14.
4 Smolen JS, Landewé R, Breedveld FC et al. EULAR rec-
ommendations for the management of rheumatoid arthritis
134
with synthetic and biological disease-modifying antirheu-
matic drugs. Ann Rheum Dis 2010;69:964–75.
5 Smolen JS, Landewé R, Bijlsma J et al. EULAR recom-
mendations for the management of rheumatoid arthritis
with synthetic and biological disease-modifying antirheu-
matic drugs: 2013 update. Ann Rheum Dis
2014;73:492–509.
6 Smolen JS, Landewé R, Bijlsma J et al. EULAR recom-
Downloaded from https://academic.oup.com/rheumatology/article-abstract/58/1/131/5090543 by Khon Kaen University user on 24 June 2020
mendations for the management of rheumatoid arthritis
with synthetic and biological disease-modifying antirheu-
matic drugs: 2016 update. Ann Rheum Dis
2017;76:960–77.
7 Sing JA, Saag KG, Bridges SL Jr et al. 2015 American
College of Rheumatology guideline for the treatment of
rheumatoid arthritis. Arthritis Rheumatol 2016;68:1–26.
8 Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF
et al. Clinical and radiographic outcomes of four different
treatment strategies in patients with early rheumatoid
arthritis (the BeSt study): a randomized, controlled trial.
Arthritis Rheum 2005;52:3381–90.
9 Verschueren P, De Cock D, Corluy L et al. Methotrexate in
combination with other DMARDs is not superior to
methotrexate alone for remission induction with moder-
ate-to-high-dose glucocorticoid bridging in early rheuma-
toid arthritis after 16 weeks of treatment: the CareRA trial.
Ann Rheum Dis 2015;74: 27–34.
10 Hazlewood GS, Barnabe C, Tomlinson G et al.
Methotrexate monotherapy and methotrexate combin-
ation therapy with traditional and biologic disease mod-
ifying anti-rheumatic drugs for rheumatoid arthritis: a
network meta-analysis. Cochrane Database Syst Rev
2016;(8):CD010227.
11 Saag KG, Teng GG, Patkar NM et al. American College of
Rheumatology 2008 recommendations for the use of
nonbiologic and biologic disease-modifying antirheumatic
drugs in rheumatoid arthritis. Arthritis Rheum
2008;59:762–84.
12 Putrik P, Ramiro S, Kvien TK et al. Variations in criteria
regulating treatment with reimbursed biologic DMARDs
across European countries. Are differences related to
country’s wealth? Ann Rheum Dis 2014;73:2010–21.
13 Carmichael SJ, Beal J, Day RO, Tett SE. Combination
therapy with methotrexate and hydroxychloroquine for
rheumatoid arthritis increases exposure to methotrexate.
J Rheumatol 2002;29:2077–83.
14 Klarenbeek NB, Güler-Yüksel M, van der Kooij SM et al.
The impact of four dynamic, goal-steered treatment stra-
tegies on the 5-year outcomes of rheumatoid arthritis
patients in theBeSt study. Ann Rheum Dis
2011;70:1039–46.
15 van der Kooij SM, de Vries-Bouwstra JK, Goekoop-
Ruiterman YPM et al. Limited efficacy of conventional
DMARDs after initial methotrexate failure in patients with
recent onset rheumatoid arthritis treated according to the
disease activity score. Ann Rheum Dis 2007;66:1356–62.
16 Fries JF, Williams CA, Ramey D, Bloch DA. The relative
toxicity of disease-modifying antirheumatic drugs. Arthritis
Rheum 1993;36:297–306.
https://academic.oup.com/rheumatology