Feature

For personal use only. Not to be reproduced without permission of the publisher (copyright@ppme.eu).

Pharmacotherapy of rheumatoid
arthritis
Judith AM Wessels, PharmD, PhD
Introduction
Rheumatoid arthritis (RA) is a chronic
inflammatory disease characterised by
joint swelling, joint tenderness, and
destruction of synovial joints, leading
to severe disability and premature mortality [1]. The treatment success of RA
has been noticeably changed with use
of disease modifying anti-rheumatic
drugs (DMARDs) and the availability
of new biological agents. With these
new therapeutic options, new questions
arise. This overview briefly presents
up-to-date treatment approaches for
patients with RA. This article is an
update of an article written by Professor Ferry C Breedveld [2]. Recently
an excellent more detailed educational
review on the use of biologicals for
rheumatoid arthritis was published by
Tugwell et al [3].

has been defined as the absence of signs

and symptoms of significant inflammatory disease activity, with either the
score on the tender joint count, swollen
joint count, C-reactive protein (in
mg/dL), and patient global assessment
(010 scale) are all below 1, or as the
score on the simplified disease activity
index is below 3.3 [5, 7].

Volume 17 2011/6

Therapy
Since RA is a syndrome with a broad
spectrum of clinical manifestations, no
single therapeutic intervention is expected to provide the best answer for all
patients. Nevertheless, new practice
guidelines with easy and conclusive
statements on initiating and adapting
drug treatment for RA patients are freely
available on the websites of the
European League Against Rheumatism
and the American College of Rheumatology [5, 8, 9]. Importantly, these
recommendations on treatment are
intended to help guide therapy and not to
exclude therapies.

Treatment strategy and therapeutic goals

No treatment cures RA, so reducing disease activity with early initiation of
DMARDs is essential in the disease
process to minimise the joint damage
and functional decline, to maximise
long-term health-related quality of life
and normalise function and social participation [4, 5]. It has been shown that
even a delay of three months in the introduction of therapy results in considerably more radiographic joint damage at
five years [4, 6]. Therefore, early referral of patients with arthritis to a rheumatologist is important and treatment
should be started directly after diagnosis
of definite RA. As an important step to
facilitate the timely diagnosis and sensitive monitoring, new RA classification
criteria have recently been developed for
patients with a relatively recent onset of
symptoms [1].
Currently, the ultimate and realistic goal
of therapy is disease remission, which

final point, tapering or even discontinuation of (biological) DMARDs is considered if disease remission is achieved and
lasts for at least several months [8, 10, 11].
Yet, if a small disease flare is noticed during
the regular monitoring visits, therapy is
again initiated.

Moreover, the strategy to achieve this

goal is close monitoring of disease activity and adjustment of therapy within
three months, even if only little disease
activity is still present [8, 9]. Validated
composite measures of disease activity,
which include joint assessments, are used
to guide these treatment decisions. As a

In general, treatment of RA usually follows a stepwise approach. The first treatment is suggested to include a synthetic
DMARD, since a significant proportion
of patients can reach very low disease
activity or remission. Methotrexate
(MTX) as initial choice is supported by
most experts, with high doses (2030 mg)
likely being more effective than MTX at
lower weekly doses (7.515 mg). It is recommended that leflunomide, sulfasalazine or intramuscular gold should be
used instead of MTX as a first DMARD,
mainly if there are contraindications to (or
intolerance of) MTX.
Antimalarials such as hydroxychloroquin are sometimes used in treating RA
patients. On the basis of their efficacy, it
is suggested that these drugs may have
some value as monotherapy in patients
with very mild disease. Yet, it is not
www.ejhp.eu

Rheumatology
clearly established if antimalarials have
additive value in DMARD combination
strategies.
The decision to combine DMARDs
largely depends on the disease activity
state and the presence of poor prognostic
factors, such as the presence of autoantibodies that is rheumatoid factor
and/or anti-citrullinated peptide antibodies, or early erosive disease. Initiation of
monotherapy is recommended for
DMARD naive patients due to the beneficial efficacy and toxicity balance. The
exception to this policy may be the addition of corticosteroids to DMARDs,
since it has been shown that corticosteroid treatment at low doses (< 10
mg/day) is valuable. However, tapering
or stopping of corticosteroids is strongly
recommended as soon as clinically feasible, with the intention to improve the
long-term safety for the patient. For
inadequate responders to DMARD
monotherapy, current recommendations
are not conclusive on the subject to combine DMARDs.
In general, the addition of biological
DMARD is normally considered if treatment goals are not achieved with first-line
monotherapy and the patient exhibits poor
prognostic factors, while switching to
another synthetic DMARD is a reasonable
option for patients without the presence of
poor prognostic factors. However, the initiation of biological DMARDs therapy is
likely also to be influenced by the licence
and insurance status of these drugs,
within Europe rituximab and abatacept
currently being licensed only for use after
failure of tumour necrosis factor (TNF)
inhibitors. To date, standard practice is
therefore to start with an anti-TNF agent:
adalimumab, certolizumab, etanercept,
golimumab, infliximab. It is noteworthy
that most biological agents are more
effective with MTXTNF inhibitors, rituximab and tocilizumab. Thus, if there is
no contraindication for MTX, the combination of DMARDs is preferred.
Finally, if the first TNF inhibitor therapy fails, another TNF inhibitor but also
abatacept, rituximab and tocilizumab
are effective treatment options. If dis Volume 17 2011/6

ease remission is achieved, tapering of

biological DMARDs may be considered. These agents should be tapered
cautiously with dose reductions or
interval expansions while continuing
synthetic DMARDs since it is more difficult to re-achieve disease remission if
a patient experiences a disease flare.
Therefore, as a next step, tapering of
synthetic DMARDs is only optional if
biologicals and corticosteroids are fully
withdrawn.

5.

6.

Next generation drugs

Despite the currently available (biological) DMARD options, approximately
one third of the RA patients experience
insufficient response to therapy. Fortunately, promising small molecules are
being developed to treat patients with
RA [12, 13]. These orally administrated
agents inhibit intracellular signaling
pathways by blocking kinases such as
mitogen-activated protein kinases,
Janus kinases and non-receptor tyrosine
kinases (Syks). Their efficacy and safety
are still in under study in phase III clinical
trials. Therefore, their place in RA therapy
is yet unclear, given that no head to
head comparisons with other (biological) DMARDs have been performed.

7.

8.

9.

Author
Judith AM Wessels, PharmD, PhD
Department of Clinical Pharmacy and
Toxicology
Leiden University Medical Center
2 Albinusdreef
NL-2333 ZA Leiden, The Netherlands

10.

References
1. Aletaha D, Neogi T, Silman AJ, Funovits J,
Felson DT, Bingham CO III, et al.
Rheumatoid arthritis classification criteria:
an American College of Rheumatology/
European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;
62:2569-81.
2. Breedveld FC. Treatment of rheumatoid
arthritis in perspective. Eur J Hosp Pharm
Prac. 2005;11(2):38.
3. Tugwell P, Singh JA, Wells GA. Biologicals for rheumatoid arthritis. Br Med J
2011;343:d4027. doi: 10.1136/bmj.d4027
4. van AJ, Lard LR, le Cessie S, Hazes JM,
Breedveld FC, Huizinga TW. Radiological
outcome after four years of early versus

11.

12.

13.

delayed treatment strategy in patients with

recent onset rheumatoid arthritis. Ann
Rheum Dis. 2004;63:274-9.
Smolen JS, Aletaha D, Bijlsma JW,
Breedveld FC, Boumpas D, Burmester G,
et al. Treating rheumatoid arthritis to target:
recommendations of an international task
force. Ann Rheum Dis. 2010;69:631-7.
Mottonen T, Hannonen P, Korpela M,
Nissila M, Kautiainen H, Ilonen J, et al.
Delay to institution of therapy and induction of remission using single-drug or combination-disease-modifying antirheumatic
drug therapy in early rheumatoid arthritis.
Arthritis Rheum. 2002;46:894-8.
Felson DT, Smolen JS, Wells G, Zhang B,
van Tuyl LH, Funovits J, et al. American
College of Rheumatology/European League
Against Rheumatism provisional definition of
remission in rheumatoid arthritis for clinical
trials. Ann Rheum Dis. 2011;70:404-13.
Smolen JS, Landewe R, Breedveld FC,
Dougados M, Emery P, Gaujoux-Viala C, et
al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis. 2010;
69:964-75.
Saag KG, Teng GG, Patkar NM, Anuntiyo
J, Finney C, Curtis JR, 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.
van der Kooij SM, Goekoop-Ruiterman YP,
de Vries-Bouwstra JK, Guler-Yuksel M,
Zwinderman AH, Kerstens PJ, et al. Drugfree remission, functioning and radiographic damage after 4 years of responsedriven treatment in patients with recentonset rheumatoid arthritis. Ann Rheum Dis.
2009;68:914-21.
Klarenbeek NB, van der Kooij SM, GulerYuksel M, van Groenendael JH, Han KH,
Kerstens PJ, et al. Discontinuing treatment
in patients with rheumatoid arthritis in sustained clinical remission: exploratory analyses from the BeSt study. Ann Rheum Dis.
2011;70:315-9.
Bonilla-Hernan MG, Miranda-Carus ME,
Martin-Mola E. New drugs beyond biologics in rheumatoid arthritis: the kinase inhibitors. Rheumatology (Oxford) 2011.
Quintas-Cardama A, Kantarjian H, Cortes
J, Verstovsek S. Janus kinase inhibitors for
the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discov.
2011;10:127-40.

EJHP is the Official Journal of the European Association of Hospital Pharmacists (EAHP)

www.ejhp.eu