Rheumatoid Arthritis (RA) is a common rheumatological disorder. Many drugs including Anti TNF agents have been used for the treatment of this condition. The result hitherto, have been excellent, but shortcomings and the absence of complete remissions even in Anti TNF treated patients, makes the trial of newer agents, targeted to novel pathophysiologic molecules, all the more important and urgent. New insights in the pathogens of RA and three new biologics for RA have been discussed.

1. New And Emerging Therapies For Rheumatoid Arthritis

2. Review Article
NEW AND EMERGING THERAPIES FOR RHEUMATOID ARTHRITIS
Sundeep Kumar Upadhyaya
Senior Consultant, Rheumatology Immunology,
Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India.
e-mail: sundeepupadhyaya@gmail.com, sundeepupadhyaya@hotmail.com
Rheumatoid Arthritis (RA) is a common rheumatological disorder. Many drugs including Anti TNF agents
have been used for the treatment of this condition. The result hitherto, have been excellent, but shortcomings
and the absence of complete remissions even in Anti TNF treated patients, makes the trial of newer agents,
targeted to novel pathophysiologic molecules, all the more important and urgent. New insights in the
pathogens of RA and three new biologics for RA have been discussed.
Key words: Abatacept, Emerging therapies, Rheumatoid arthritis, Rituximab, Tocilizumab.
INTRODUCTION
persistent inflammatory reaction is established in the
joint, sustained remissions despite drug therapy are the
exception rather than the rule. It is likely that current
therapies are targeting common inflammatory pathways
downstream of the inciting events. These pathways
therefore appear not to be unique to RA but are common
to several autoimmune inflammatory diseases. Many such
diseases thus also respond to DMARDs and biologics
used for the treatment of RA (e.g. ulcerative colitis). That,
anti TNF- products are extremely effective proves the
fact that TNF- is an important pro-inflammatory
cytokine driving the inflammatory response in RA [4]. It
is noteworthy that anti IL-1 products have yielded
disappointing results. Therefore, not all cytokines
expressed in the rheumatoid synovium are necessarily
viable therapeutic targets. However, the results from
clinical trials in the management of RA using anti IL-6
and anti IL-15 are encouraging. Thus, targeting these
cytokines for the management of RA is logical. Although,
anti-CD4, anti-CD5 and anti-CD52 products have failed
to produce significant benefits in RA management
(indicating that curbing T-cell activity alone is not the
solution), abatacept or CTLA4-Ig which blocks the
stimulation of naïve T cells, has been found to be
extremely effective in RA treatment. Activated T cells
have been seen in contact with macrophages; this cell-cell
contact has been shown in vitro to induce synovial
fibroblast and macrophages to secrete damaging
cytokines [5] (Fig.1). The B-cell is also a therapeutic
target largely based on the success of Rituximab therapy
for RA [6]. About 50% of patients who have RA, B-cells,
T-cells and dendritic cells organize themselves into
follicular structures resembling germinal centres [7].
When rheumatoid synovitis is reconstituted in special
mouse models of RA, B-cell depletion disrupts the
ANTI-TUMOR necrosis factor agents for the treatment of
rheumatoid arthritis (RA) have been in use both clinically
and in trials for more than ten years. They are extremely
effective and have hitherto been used in patients who have
failed multiple conventional DMARDs like Methotrexate
and Leflunomide. They achieve ACR 50 and ACR 70
clinical responses in a sizable number of patients and are
widely available in all developing countries including
India. Radiographic joint damage occurs in patients with
rheumatoid arthritis (RA) in nearly 75% within the first 2
years of disease [1]. Currently RA treatment approaches
are focused on early intensive therapy with multiple
disease modifying drugs (DMARDs). Methotrixate
(MTX) is the first choice DMARD and often the anchor
drug for combination regimens. An increasing proportion
of patients are receiving newer DMARDs like leflunomide
and biologics like anti TNF- products (etanercept and
infliximab) since the response rates with MTX alone are
poor. Indeed, combined use of MTX and an anti TNFproduct is among the most potent treatments for RA. Yet,
clinical trials of early RA treatment show that this
combination generates ACR70 responses of only 35-45%
[2,3]. The desired role of DMARD therapy is thus not
realized in most treatment regimens and these
shortcomings of currently approved therapies highlight the
need for investigating new strategic approaches and novel
drugs. This article reviews the new biologic therapeutic
agents available for treatment in India.
New insights into RA pathogenesis
The failures and successes of new drugs evaluated for
the treatment of RA have provided new insights into the
mechanisms underlying the disease pathogenesis. Once a
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3. Review Article
Fig.1.
Role of T cells in rheumatoid arthritis pathogenesis.
Antigen-presenting cells (ACPs) present processed
peptide to the TCR, which recognizes the peptide
within the context of the MHC molecule. Other
receptors must also be activated for full T-cell
activation to happen; these are represented by the
molecules schematically depicted on the surface of
ACPs, T cells synovicytes, and B cells. (Adapted from
J.M. Kremer).
Fig.2
tertiary lymphoid micro-structure and diminishes T-cell
activity/response [8]. Thus B-cell depletion may reduce Tcell activation and is a very important method for
controlling inflammation in RA.
to receive either placebo (n=119) or abatacept, 2mg/kg
(n=105) or 10mg/kg (n=115), intravenously, at days 1, 15
and 30 and monthly thereafter for 12 months [9,10]. At six
months, the group receiving 10mg/kg of abatacept had a
bigger ACR 20 response rate than the placebo group (60%
vs.35%). These responses were maintained at 12 months.
However, the ACR 20 responses in the 2mg/kg group were
not different from the placebo, indicating that 10mg/kg
per dose is the optimal dose for the treatment of RA.
Targeting the T-cell: Cytotoxic T-lymphocyte
antigen 4-immunoglobulin (CTLA4-Ig):
Abatacept
CTLA4-Ig represents a new class of molecules that
blocks the second stimulus for T-cell activation. Resting Tcells require two separate signals for full stimulation. The
first signal is the interaction of the processed peptide in the
major histo-compatibility (MHC) with the T cell receptor
(TCR). The second signal is the engagement of the CD-28
on T-cells with the CD80/86 (B7-1 or B7-2) on the surface
of the antigen presenting cell (Fig.2). CTLA 4 is a second,
high affinity receptor for both CD80 and CD86, binding
up-to a 1000 times as avidly to the B7 members as CD 28.
The binding of CTLA 4-Ig to the B7 molecule thus
prevents the interaction between CD80/86 and CD28,
essentially blocking the second signal for T-cell activation
(Fig. 2).
In another recent trial, 393 patients who had an
inadequate response to anti TNF- therapy plus MTX/
other DMARD, were randomized in a ratio of 2:1 to
receive a fixed dose of abatacept (500mg, 750mg, or
1000mg) at days 1, 15, 29, and then every 28 days through
day 141 [11]. At six months, the abatacept group was
superior to the placebo group (ACR 20) was 50.4%
vs.19.5%; P<0.001).
Abatacept may also be used in patients who have had
an inadequate response to MTX mono-therapy. In a study
involving 652 patients on stable MTX doses, patients were
randomly allocated in a 2:1 ratio to receive abatacept in a
fixed dose of 10mg/kg on days 1, 15, 29 and then every
28 days through day 141 [12]. At 12 months, ACR 20, 50
and 70 response rates were higher in the abatacept group
than the placebo group (80% vs. 60%, 53.3% vs. 33.8%,
and 26.7% vs. 12.7%, respectively; P<0.001 for all
comparisons between abatacept and placebo groups).
There was also data generated to show a reduced
radiographic progression in the abatacept group [13].
CTLA4-Ig or Abatacept is the fusion protein
consisting of cytotoxic T-lymphocyte associated antigen 4
(CTLA 4) covalently linked to the Fc region of a human
IgG1 molecule (Fig.3). Several large clinical trials have
proven the efficacy of CTLA4-Ig in the treatment of RA.
In one early study, 339 patients who had active RA despite
receiving optimal doses of MTX, were randomly allocated
Apollo Medicine, Vol. 6, No. 1, March 2009
Mechanism of action of the CTLA4-Ig molecule.
Because CTLA4 binds to CD80/CD86 with much
greater avidity than CD28 (and CD28 binds to both
CTLA4 and CD80/CD86), the presence of the artificial
construct molecule will also selectively bind CD28,
thus preventing full T-cell activation as well as
subsequent B cell activation. (Adapted from J.M.
Kremer)
52

4. Review Article
Fig 3.
Schematic representation of the structure of the
CTLA4 molecule. A human CTLA4(CD152) transmembrane protein is fused with an IgGI Fc molecule
to make the CTLA4-Ig, which is given intravenously.
Fig. 4. Articular effects of IL-6.
The toxicity profile of abatacept has been very favorable
[14].
IL-6 inhibition is clinically achieved by blocking the
IL-6 receptor (IL-6R). In a placebo controlled trial using a
recombinant, humanized, monoclonal antibody against
the IL-6R receptor (tocilizumab). In patients with
refractory RA, ACR20 and ACR50 responses were
achieved in 78 and 40% respectively [17]. Mild elevations
of cholesterol and moderate elevations of liver enzymes
were observed in the tocilizumab group. In another study
patients with disease duration of less than 5 years were
randomly allocated to receive either tocilizumab, 8mg/kg,
intravenously every 4 weeks or another conventional
DMARD (MTX but not leflunomide/biologics) [18]. At
52 weeks the tocilizumab group showed less radiographic
progression than the conventional DMARD group. The
ACR20, ACR50 and ACR70 responses were 89%, 70%
and 47% vs. 35%, 14% and 6% in the tocilizumab and
DMARD groups, respectively.
Targeting the B-cell: Rituximab (anti CD20
monoclonal antibody)
CD20 is expressed on the B-cells from the pre-B cell
through the mature stage, but is absent on stem cells and
plasma cells. Rituximab eleminates B-cells by binding to
CD20, and causes an antibody-dependent cellular cytotoxicity, which finally leads to a transient depletion of
CD20 positive B-cells. Several large clinical trials have
proven the efficacy and safety of Rituximab for RA. In one
early clinical trial (randomized, double blind, controlled
study) involving rituximab alone, MTX alone, rituximab +
cyclophospha-mide, and rituximab + MTX, most of the
ACR20 and ACR 50 responses were significantly lesser in
the MTX only group vs. all the other rituximab groups [6].
Adverse events in the form of hypotension, hypertension,
cough, pruritis and rash were related to the first
inflammations in the rituximab groups.
SUMMARY
The new anti rheumatic/biologic drugs will bring new
therapeutic possibilities and challenges for the treatment
of RA. These new agents will allow the clinician to use
novel induction regimens, combination therapies, and
tailor-made therapies for the individual RA patient. New
potent induction regimens may allow drug free holidays to
become a realistic goal, thus mitigating the possible side
effects of long term immuno suppressive drugs. For e.g. in
the BeST study 56% of 120 patients who started the
treatment of early RA with infliximab in combination with
MTX were able to maintain a low disease activity even
after stopping infliximab [19]. These and other
encouraging results will provide motivation for similar
induction regimens in early RA.
Rituximab has also been investigated as an option for
RA patients who have failed anti TNF- therapy. In one
clinical trial patients who had failed concomitant MTX
(10-25mg/wk) and anti TNF- therapy, subjects were
randomized to receive rituximab or placebo [15]. ACR20
and ACR 50 responses were significantly better in the
rituximab group.
Targeting a
tocilizumab
specific
cytokine:
Anti
IL-6,
IL-6 is another cytokine which plays an important role
in the pathogenesis of RA (Fig.4). IL-6 is abundantly
expressed on T-cell, macrophages and fibroblasts in the
rheumatoid synovium. More importantly, serum IL-6
concentrations have been shown to correlate with disease
activity and radiological joint damage [16].
MTX monotherapy may not survive as the acceptable
standard of care for the treatment of RA since most recent
studies feature combination regimens. Pioneering
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5. Review Article
treatments for early and moderate RA are no just emerging
therapies for this condition, they qualify as current
therapies.
rheumatoid arthritis refractory to tumor necrosis factor
inhibition.N Engl J Med 2005; 353: 1114-1123.
12. Russell A, Shergy W, Numah I, et al. Abatacept treatment
demonstrates rapid, consistent and sustained increases
in ACR response rates over 1 year in patients with active
rheumatoid arthritis. Presented at EULAR 2005. Vienna,
Austria, June 8-11, 2005. Available at:http://
www.abstaracts2view.com/eular. Accessed January 2,
2006.
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