254
P A R T 3
Drugs acting on the immune system
of inflammation. Because they alter the course of the
inflammatory process, many rheumatologists are select-
ing to use DMARDs early in the diagnosis, before
damage to the joints has occurred. Adverse effects asso-
ciated with these drugs (see Adverse effects) can be severe
to life-threatening because they alter the ability of the
body to initiate or carry on an inflammatory reaction.
DMARDs discussed in this chapter include drugs
used when people do not respond to conventional
therapy—anakinra (
Kineret
), etanercept (
Enbrel
),
leflunomide (
Arava
) and penicillamine (
D-Penamine
)—
and drugs used to directly decrease pain in joints
affected by arthritis, including hyaluronidase derivative
(
Hyalase
) and sodium hyaluronate (
Fermathron
).
Additional drugs also used to modify the disease
process in rheumatoid arthritis include the antineoplas-
tic drug methotrexate (see Chapter 14), the monoclonal
antibodies infliximab (
Remicade
), golimumab (
Simponi
)
and adalimumab (
Humira
) (see Chapter 17), the T cell
suppressor abatacept (
Orencia
) (see Chapter 17), certain
antimalarial drugs (see Chapter 12), some additional
antineoplastic drugs such as cyclophosphamide (see
Chapter 14) and the immune modulators cyclosporin A
and azathioprine (see Chapter 17).
Therapeutic actions and indications
Anakinra is one of the newest of the antiarthritis drugs.
This drug is an interleukin-1 receptor antagonist. It
blocks the increased interleukin-1, which is responsible
for the degradation of cartilage in rheumatoid arth
ritis. This drug must be given each day by subcutaneous
injection and is often used in combination with other
antiarthritis drugs.
Etanercept contains genetically-engineered tumour
necrosis factor (TNF) receptors derived from Chinese
hamster ovary cells. These receptors react with free-
floating TNF released by active leucocytes in auto-
immune inflammatory disease to prevent the damage
caused by TNF. See Table 16.3 for usual indications.
Hyaluronidase derivatives, such as hylan G-F 20 and
sodium hyaluronate, have elastic and viscous properties.
These drugs are injected directly into the joints of people
with severe rheumatoid arthritis of the knee. They seem
to cushion and lubricate the joint and relieve the pain
associated with degenerative arthritis. They are given
weekly for 3 to 5 weeks.
Leflunomide directly inhibits an enzyme, dihydro-
orotate dehydrogenase (DHODH), which is active in the
autoimmune process that leads to rheumatoid arthri-
tis, relieving signs and symptoms of inflammation and
blocking the structural damage this inflammation can
cause, slowing disease progression.
Penicillamine lowers the immunoglobulin M (IgM)
rheumatoid factor levels in people with acute rheum
atoid arthritis, relieving the signs and symptoms of
inflammation. It may take 2 to 3 months of therapy
before a response is noted.
Pharmacokinetics
Anakinra is slowly absorbed from the subcutaneous
tissue, reaching peak levels in 3 to 7 hours. It is meta
bolised in the tissues and excreted in the urine. It has
a half-life of 4 to 6 hours. Etanercept is very slowly
absorbed after subcutaneous injection, reaching peak
levels in 72 hours. It is metabolised and destroyed in the
tissues with a half-life of 115 hours. The hyaluronidase
derivatives are not absorbed systemically. Leflunomide
is slowly absorbed from the GI tract, reaching peak
levels in 6 to 12 hours. It undergoes hepatic metabolism
and excretion in the urine. The half-life of leflunomide is
14 to 18 days. Penicillamine is an oral drug that reaches
peak levels in 1 to 3 hours after administration. It is
extensively metabolised in the liver and excreted in the
urine with a half-life of 2 to 3 hours.
Contraindications and cautions
These drugs are contraindicated in the presence of
allergy to the drugs or to the animal products fromwhich
they were derived (Chinese hamster products in etaner
cept; chicken products in hylan G-F 20 and sodium
hyaluronate); pregnancy or breastfeeding
because of the
potential for adverse effects on the fetus or neonate
;
acute infection
because of the blocking of normal
inflammatory pathways
; and liver or renal impairment,
which could be exacerbated by these drugs.
Adverse effects
A variety of adverse effects are common with the use of
these drugs, including local irritation at injection sites
(anakinra, etanercept, hyaluronidase derivatives and
sodium hyaluronate), pain with injection and increased
risk of infection. Leflunomide is associatedwith potentially
fatal hepatic toxicity and rashes. Penicillamine is associ-
ated with a potentially fatal myasthenic syndrome, bone
marrow depression and assorted hypersensitivity reac-
tions. Etanercept is associated with severe bone marrow
suppression, and a warning has been issued stating that
the drug has been associated with the development of
serious CNS problems, including multiple sclerosis. It can
also cause severe myelosuppression and increased risk of
infections and cancer development. People who use this
drug need to be monitored very closely. Leflunomide
has been associated with severe hepatic toxicity, and the
person’s liver function needs to be monitored closely.
Clinically important drug–drug interactions
Hyaluronidase derivatives such as sodium hyaluro-
nate should not be injected at the same time as local
anaesthetics.
