open access: Nature Reviews: Key Advances in Medicine

RHEUMATOLOGY
Treatment population Treatment options
Treatment goal
ACPA-positive
ACPA-negative
Figure 1 | Treatment flow in RA. After diagnosis, it might be important to further stratify a patient
with RA according to ACPA status. A variety of treatment options then exist for RA. Tyrosine
kinases represent promising new agents that might be efficacious in the treatment of RA. The
ultimate aim of treatment is to induce a state of remission. Abbreviations: ACPA, anti-citrullinated
protein antibodies; CRP, C-reactive protein; PtG, patient global assessment score; RA, rheumatoid
arthritis; SDAI, simplified disease activity index; SJC, swollen joint count; TJC, tender joint count.
Tofacitinib binds to and inhibits the important
intracellular enzymes JAK1, JAK2 and
JAK3, which are involved in immune cell activation,
production of proinflammatory cytokines
and cytokine signaling. A major step
towards the introduction of tofacitinib to the
clinic was made in 2011 with the publi cation
of the results of a phase IIb, 24-week, doubleblind,
randomized controlled trial of this
compound by Fleischmann et al. 5 The patient
populations enrolled in this study comprised
indivi duals with RA and an inadequate
response to DMARDs, who were assigned to
receive monotherapy of various dosages of
tofacitinib, the TNF inhibitor adalimumab or
placebo. Treatment with tofacitinib resulted
in a rapid clinical response, with ACR 20%
improvement criteria (ACR20) response at
week 12 ranging from 59.2% (5 mg) to 71.9%
(15 mg), and the response was maintained at
24 weeks. 5 By contrast, ACR20 was achieved
by 22% of the placebo group and an adalimumab
response rate of 35.9% was recorded
—notably, the latter drug was also used
as a monotherapy without metho trexate. 5
Markedly improved ACR50 and ACR70
responses as well as disease activity score in
28 joints (DAS28) remission were observed
for tofacitinib, compared with placebo. 5 The
adverse events associated with tofacitinib
treatment included urinary tract infections,
diarrhea and anemia. 5 These data confirmed
the efficacy of tofacitinib, and have led to the
initiation of a large phase III program for this
drug in patients with RA.
Thus, the therapeutic options available to
rheumatologists could soon be increased by
the addition of new orally administered small
molecules, especially when one con siders
that fostamatinib, another tyrosine kinase
inhibitor that targets spleen tyrosine kinase
(Syk), has also demonstrated con siderable
Glucocorticoids
Conventional DMARDs
Cytokine inhibition
B-cell depletion
Inhibition of costimulation
Inhibition of tyrosine kinases
Remission (de�ned by TJC,
SJC, PtG and CRP [mg/dl]
all ≤1, or SDAI ≤3.3)
efficacy in RA. 6 Naturally, important questions
remain unanswered, particularly with
regard to long term safety in the ‘real world’,
where these agents will be used in combination
with a multitude of other drugs that treat
comorbid diseases. Moreover, it remains to be
seen whether doctors and patients will prefer
60 tablets per month over a syringe that can
be self- administered once a week, or even
once per month.
The introduction of new treatment modalities,
such as tofacitinib and fostamatinib,
could help us to reach our current goal in
RA therapy, namely a state of remission,
particularly if a treat-to-target approach is
used. 7 However, what does ‘remission’ really
mean? Last year, a group of American and
Euro pean experts came together to explore
this important question and to generate a
stringent definition of this state of minimal
disease activity. 8
On the basis of the evidence from large
trials that analyzed the development of
radiologically evident joint destruction
or loss of function, the panel representing
ACR–EULAR came up with a definition for
remission, 8 in which a number of different
individual disease activity measures are considered
together. Using this approach, remission
is said to be achieved when the number
of tender and swollen joints, the level of CRP
(mg/dl) and the patient global assessment
score (0–10 scale) are all ≤1. 8 An alternative
definition is an SDAI (simplified disease
activity index) of not more than 3.3. 8 In clinical
practice and in trials, these definitions
have been applied successfully. 9,10 However,
to achieve a patient global assessment of ≤1
will be a challenge. Although the goals set
by ACR–EULAR are demanding, the 2011
remission criteria define clear targets for the
management of patients with RA and will
probably change our approach to treating this
debilitating disease, especially immediately
after onset.
As a result of key breakthroughs made in
2011, we are now able to define RA much
more effectively, we could soon have new
thera peutics at our disposal and we have clear
goals to aim at when treating patients with
this previously devastating disease (Figure 1).
Hope fully, the progress made last year will
improve patient care and lead to further
evolution of the field in 2012 and beyond.
Department of Rheumatology and Clinical
Immunology, Charité-Universitätsmedizin
Berlin, Charitéplatz 1, 10117 Berlin, Germany.
gerd.burmester@charite.de
Competing interests
The author declares associations with the following
companies: Abbott and Pfizer. See the article online
for full details of the relationships.
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