Biologics in Rheumatoid

Arthritis
Dr. Zuhair N. Sabbagh M. D

Rheumatology & Rehab.

R. C . P . London R .C . S . England
President Of PAN – ARAB ASSOCIATION FOR Rheumatic
Diseases
The Medical Centre Sukina Building
Jabal El- Hussein
Tel :+ 962 – 79 -552 1250
P.O.Box : 940064
Amman 11194 Jordan
Email : zuhairsabbagh@hotmail.com

Biologics in Rheumatoid Arthritis

The introduction of biologic agents revolutionized Rheumatoid

Arthritis treatment in recent years; there success has underlined
the key roles of inflammatory cytokines in Rheumatoid Arthritis
pathogenesis ; particularly the rules of Tumor Necrosis Factor
TNF - and IL -1.
The complex interaction of cytokines and the multiplicity of
cytokine targets mean that it is difficult to predict the
effectiveness and the toxicity of cytokines – based intervention

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either by neutralizing cytokines using soluble receptors of
monoclonal antibodies or receptor blocked …..etc.
Different immunotherapeutic approaches tested during the
1990s outlined in table 1; these with the exception of therapies
targeting TNF - or to lesser extent IL – 1 were ultimately
unsuccessful , however further biologics being evaluated as
T.cell co-stimulation blocker, anti IL-6 monoclonal antibody,
antibody targeting CD20 + B cells. All aimed for long term
remission or god wish for permanent remission.
Tumour necrosis factor – alpha is produced primarily by
monocytes & macrophages and also by activated T.cells, B.cells,
& fibroblast , it can modulate growth, differentiation , &
metabolism in a variety of cell types, initiate apoptosis in
malignant or transformed cells & also powerful inducer of
inflammatory response.
Further more, TNF is considered to be a central regulator of
innate immune response.
Rheumatoid Arthritis Immunopathology
Rheumatoid Arthritis immunopathology begins when an antigen
presenting cells (APC) activates a T.lymphocyte (T.cell),
activated T.cell are the main orchestrator in R.A –
immunopathology.
Full activation of T.cell requires two signals by (APC) 1st signal
is antigen specific , an antigen is presented on the surface of
(APC) by a major histocompatibility complex (MHC) molecule,
this MHC/Antigen complex must be recognized by an antigen-
specific T-cell receptor (TCR).
The 2nd signal occurs when a co-stimulatory molecule on the
surface of the T.cell bind to a complementary co-stimulatory
molecule on the surface of (APC).Without this 2ndry co-
stimulatory molecule, T.cell activation leading to proliferation &
differentiation will not occur. (1,2)
Activated T.cell induces the activation of B.cells, macrophages,
moncytes & fibroblasts and also secretes cytokines like TNF-
& interleukin 2 (IL-2) and B.cells then stimulate the production
of Rheumatoid factor (RF), an autoantibody commonly found in
patients with RA.

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Activated macrophage secrete a range of cytokines including
TNF- , IL-1 & IL-6
Both TNF - & IL-1 are found elevated in synovial tissue of
patients with RA, cytokines released by macrophage, the
stimulated synovial fibroblast, osteoclast and chondrocytes
known to release tissue – destroying metalloproteinase , these
mesenchymal cells causes bone degradation & lead to joint
damage, cytokines induce inflammation and joint swelling and
further activate more T.cells, B.cells, and macrophages causing
continuous destructive cycle that begin with T.cell activation.
Biologic DMARDS employ various method to interfere with the
action of autoimmune cells & proinflammatory cytokines,
including the use of monoclonal antibodies (chimeric or fully
human), soluble receptors, binding protein, & receptor
antagonists.
Anti-TNF treatment employ mechanisms such as receptor fusion
protein & monoclonal antibodies to target both soluble & memb
bound TNF- & TNF-B, & interfere with receptor binding of
TNF cytokine.
Currently, there are three TNF- inhibitors that can be used to
treat RA (tab.4) Despite the difference between them all these
TNF inhibitors have relatively rapid onset of action in the
majority of patients improving within few weeks.
Despite this prompt & continued response, majority continue on
long term treatment due to lack of free remission.(3.4)
Clinical use:
There is no evidence that anyone use TNF blocker is more
effective than any other (128-133).
Studies suggest that failure to respond to any one TNF blocking
agent does not preclude response to another (category B, D.
evidence 128-133) individually important responses including
patients oriented measures or physical measures for e.g. Joint
tenderness should be demonstrated within treatment 12 weeks
for RA. If such improvement occurs, they should be continued
.If patients show no response they should be stopped.(6 – 17)
(5.6)
Infections:

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An increased susceptibility to tuberculosis or reactivation of
latent tuberculosis should be considered a class characteristic of
TNF blocking agents; the clinical picture of TB may be atypical
for e.g. military or extra pulmonary presentation.
No head to head comparisons of TNF blocking agents have been
done about the incidence of reactivation of latent tuberculosis.
Screening of patients about to start TNF blocking agent has
reduced the risk of activating TB.138 of patients should be
evaluated for possibility of latent TB including history of prior
exposure prior or active drug addiction, HIV infection , birth or
living in region of high prevalence of TB, physical exam &
screening test as skin test & chest x-ray.
Serious bacterial infections has been observed but its not clear
for the most part that their incidence is higher than in patients
with RA using other than DMARD or corticosteroid therapy.
TNF blocking agents should not be started as should be
discontinued when severe infection occur as septic arthritis,
infected prosthesis acute abscess, osteomyelitis, systemic fungal
infection…etc.(7.8).
Injection site, infusion reaction: injection site reaction
(etanercept, adalimumab) & infusion reaction (infliximab) occur
in patients receiving administered these agent more than
controls and are usually mild-moderate (9-10).
Malignancies: incidence of lymphoma is increased in RA
particularly in RA with high disease activity TNF blocking
agents used in RA appear to be associated with an approximate
doubling of the risk of non-Hodgkin’s lymphomas relative to the
risk in patients with rheumatoid arthritis. There is no evidence
that TNF blocking agents are associated with an increased
incidence of other malignancies.
Hematological: A few rare instances of pancytopenia & plastic
anemia has been reported (11,12).
Pregnancy: There is no sufficient data to advice continuing or
starting of anti TNF therapy in pregnancy, but small pharma
covigilance studies have not shown that rates of normal live
births, miscarriages & therapeutic termination (13) are different
from published rate for the normal population .

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Autoimmune – like syndrome:Rare cases of syndromes
resembling drug induced lupus have occurred in patient
receiving TNF blocking agents , treatment should be
stopped.(14.15.16.17).
There is no evidence that patient with RA who had or developed
positive ANA, acl & ords – DNA are at significantly increased
risk for development of drug induced lupus (7.12.15)
Demyelinating like disorder & optic neuritis have been reported
although its not known if its different from a comparable group
of patients with RA who have not received TNF- blocking
agents; so patient with such disorder should not receive TNF
blocking agents .
IL-1 Blocking agents:Anakinra has reached the market, the use
of IL-1 blocking agents as the first DMAD should at present
limited , because no trial in early RA have been performed.
There are observational data that IL-1 ra is effective in patient
failing TNF blocking therapy.
Injection site occur in 70% of patients does not require
treatment.
Etanercept:
Etanercept is a recombinant soluble p75 TNF-receptor-Fc fusion
protein.It is comprised of two dimmers; each has an
extracellular, ligand-binding portion of the higher-affinity type 2
TNF receptor(p75), which is linked to the Fc portion of human
IgG1.This fusion protein binds to both TNF- and TNF-B and
prevents them from interacting with their receptors.Etanercept is
administered subcutaneously at a dose of 25 mg twice a week or
50 mg once weekly. This dosing reflects its half-life of about 4
days.It can be given alone or in combination with other
DMARDS, such as methotrexate, to enhance efficacy.

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Infliximab:
Infliximab is a chimeric IgG1 anti TNF- antibody in which the
antigen binding region is derived from a mouse antibody and the
constant region originates from a human antibody. It binds to
soluble and membrane-bound TNF- with high affinity,
blocking the binding of TNF- to its receptors.
Infliximab also kills cells that express TNF- through antibody
–dependent and complement-dependent cytotoxicity. There is
considerable inter-patient variability in the pharmacokinetics of
infliximab. The standard dosage is 3mg/kg every 8 weeks.
However, trough concentrations at 8 weeks after a standard dose
vary enormously between patients. Shortening the interval
between doses may be more effective than increasing the dose in
raising the trough levels, although either approach can be
utilized. Unlike the other two anti-TNF agents, where
concomitant DMARD therapy is optional and designed to
improve efficacy, infliximab must be given with methotrexate.
This is recommended to prevent the formation of human
antichimeric antibodies( antibodies against the mouse part of the
chimeric molecule)which are associated with a higher rate of
infusion reactions. Such antibodies also reduce the half-life of
infliximab, but to date this has not proved to be associated with
reduced efficacy in practice.
Adalimumab:
Adalimumab is a recombinant human monoclonal anti-TNF-
antibody. It binds to human TNF- with high affinity and, as a
consequence, stops the cytokine binding to its receptors.
Adalimumab also lyses cells that express TNF- on their
surface. The drug is given by subcutaneous injection. The
absorption rate is slow; peak concentrations are achieved after
120 hours. Although the absorption rate differs between
patients, adalimumab is usually given fortnightly ; it can be
given alone or in conjunction with other DMARDs to enhance
efficacy

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Efficacy:
TNF- inhibitors, when given in adequate doses, produce major
Improvements in symptoms, signs and laboratory measures of
RA. This improvement occurs within 12 weeks of starting
treatment. There is no evidence that any particular TNF-
inhibitor is more effective than any other. As such, any agent can
be chosen as initial therapy. Benefit from switching to another
TNF- inhibitor when the first has failed is well documented,
though not supported by evidence from clinical trials
Individually important responses should occur within 8 – 12
weeks. Treatment should not be continued if there is no
evidence of benefit. In patients with an incomplete response,
increasing the dose or reducing dosing intervals may provide
additional benefits, as may the addition or substitution of other
DMARDs.
There is growing evidence that TNF- inhibitors slow or
prevent radiographic progression in RA, particularly in early
RA. Combined therapy using methotrexate and a biologic is
associated with an even greater reduction in the rate of
progression . However, though erosive radiological damage is
one of the best markers of ultimate disability levels, the long-
term clinical relevance of slowing radiological damage remains
are uncertain in terms of the degree of disability prevented.
Therefore, influencing radiographic progression should not be
the only factor influencing clinical decision making.

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