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Box 9.2
Mechanism of action of corticosteroids: focus on the immune response
Cytosolic
4
receptor
7
Immediate
non-genomic
effects
Nucleus
GRE
5
Target
gene
DNA
6
Corticosteroid
drug
1
2
+
3
Plasma
membrane
Figure b Mechanism of action of corticosteroids.
e mechanism of action of corticosteroids is
outlined in Figure b. (1) Corticosteroids dier from
many drugs; their lipophilic properties enable them
to pass through the plasma membrane to enter cells.
(2) Here they bind to intracellular class I nuclear
receptors (see Chapter 2, Section 2.2.6). ese
receptors reside in the cytoplasm, reversibly bound to
proteins, and to the cytoskeleton of the cell. (3) e
ligand–receptor complexes pair together to form
homodimers, and these are then translocated to the
nucleus. (4) e active steroid–receptor complex
binds to specic regions of the DNA, known as
glucocorticoid-responsive elements (GREs). ese
are located in promoter regions of an array of target
genes whose expression is regulated by this
interaction with the steroid–receptor complex.
mRNA
Induction
Anti-inammatory
proteins
Inhibition
(5) e glucocorticoid-responsive elements can be
positive, in which case transcription of the gene is
induced. Positive elements regulate the expression of
anti-inammatory proteins, whose levels therefore
rise. (6) Where the glucocorticoid-responsive element
is negative, the target genes are repressed; their
transcription is reduced, and so levels of the encoded
pro-inammatory proteins fall. In addition, a number
of genes are aected indirectly by the interaction of
the corticosteroid–receptor complex with other
transcription factors, such as nuclear factor B (not
shown). (7) It has recently been recognized that
corticosteroids exert more immediate non-genomic
eects through activation of cytosolic receptors and
second messenger pathways. One such example is the
activation of annexin-1 (see below), which occurs
No mRNA
Repression
Inammatory
proteins
Box 9.2 Mechanism of action of corticosteroids: focus on the immune response
within minutes of ligand–receptor interaction,
compared with the much slower eects on protein
levels resulting from interference with gene
transcription. All of these mechanisms will
• Decreased adhesion
• Decreased migration
• Inhibition of activation
Macrophage
• Decreased activation
Fibroblasts
• Decreased activation
Increased production of
Corticosteroids
contribute to the overall clinical eect of
corticosteroid drugs, which are eective in
suppressing both the early and late phases of the
inammatory response.
Neutrophils
annexin-1
T- cells
Inhibits phospholipase A
Inhibits transcription
of genes for
cyclo-oxygenase
Decreased production
of inammatory mediators
(prostanoids and
cytokines)
2
• Decreased collagen
formation
Figure c Effects of corticosteroids on the cellular components and mediators of the immune
response.
e anti-inammatory actions of corticosteroids are
mediated by eects on key immune cells, and on the
production of mediators of the inammatory
response. e expression of a vast number of genes is
aected; this is illustrated in the simplied scheme
presented in Figure c. Central to the anti-inammatory
actions of corticosteroids are the decreased levels of
pro-inammatory eicosanoids (leukotrienes and
prostanoids). is decrease is achieved in part through
repression of the gene encoding cyclo-oxygenase 2,
leading to reduced synthesis of prostanoids
(thromboxane A2 and prostaglandins).
Corticosteroids also reduce the levels of prostanoids,
together with leukotrienes, through the immediate
non-genomic activation of annexin 1 (also called
• Decreased activation
• Reduced proliferation
lipocortin-1). Annexin-1 is a Ca2+-dependent inhibitor
of phospholipase A2, the enzyme catalysing the
rate-limiting step in the generation of eicosanoids.
e decreased levels of inammatory mediators in
turn limit the activation of further immune cells,
including macrophages, T-cells, and neutrophils,
thereby reducing their contribution to the
inammatory process.
e powerful and wide-ranging nature of
corticosteroid actions on the immune system also
account for some of their unwanted eects, which can
limit the clinical usefulness of these drugs. ese
include an increased susceptibility to infection, and a
slowing of wound healing due to the suppression of
collagen formation by broblasts.
224 Chapter 9 Rheumatoid arthritis
Penicillamine?
Rheumatoid factor
(auto-antibodies)
B-cells
Azathioprine
Cyclophosphamide
Leunomide
Sulfasalazine?
Tofacitinib
Rituximab
Interleukins
Interferon-γ
T-cells
Methotrexate
Anakinra
Interleukin-1
Macrophages
Antimalarials?
Methotrexate
Abatacept
Methotrexate
Ciclosporin
Gold?
Penicillamine?
Tumour necrosis factor
Gold?
Etanercept
Adalimumab
Iniximab
Certolizumab
Golimumab
Figure 9.5 Sites of action of disease-modifying anti-rheumatic drugs.
The cellular and molecular targets for the individual drugs are indicated; the mechanism of action of some
drugs has not been determined unequivocally, while others (e.g. methotrexate) have a number of targets.
eects in rheumatoid arthritis. ese include a reduction
in phagocytosis, and inhibition of the action of a number
of key cytokines, including IL-2 and TNF-. Additional
eects of methotrexate treatment, not mediated by
adenosine, include the following.
• Inhibition of the activity of IL-1, a key regulatory
cytokine in the disease process. is may be due to
decreased synthesis of IL-1 by macrophages, or through
inhibition of binding to its receptor. Alternatively, the
transcription of IL-1 receptor antagonist (IL-1ra) may
be promoted; this molecule blocks the action of IL-1 at
its receptor.
• Increased levels of the inhibitory cytokines IL-4 and
IL-10.
• Inhibition of lymphocyte proliferation and/or
increased apoptosis of T-cells.
absorption, it is taken up into cells by folate transporters
and some of the molecules undergo conversion to
methotrexate polyglutamates; these long-lived derivatives
may be responsible for the drug’s anti-rheumatic eect,
explaining why a weekly dose of the drug is able to have a
sustained eect. Methotrexate is cleared from the blood
rapidly, excreted primarily in the urine, and is both
ltered and actively secreted into the proximal
convoluted tubule by the organic anion transporter 3
(OAT3). is transporter is inhibited by NSAIDs, resulting
in increased levels of methotrexate. At doses of
methotrexate <20 mg/week, however, the combination is
generally safe, but patients should still be carefully
monitored for adverse eects. Methotrexate is taken
only once a week, orally or by subcutaneous injection.
Patients are at risk of severe toxicity in the case of
accidental overdose, for example by taking the drug daily.
Methotrexate is well absorbed, although its bioavailability
and toxicity vary widely between patients. Following
Side eects Because of its cytotoxic eects any rapidly
dividing cells can be aected by methotrexate. ese
9.4 Disease-modifying anti-rheumatic drugs (DMARDs) 225
include stem cells in the bone marrow, liver cells, and
mucosal cells lining the gastrointestinal tract. Nausea and
stomatitis (inammation of the lining of the mouth) are
the most common side eects, but these can usually be
managed by giving low dose folic acid, or by dividing the
dose across the day. Patients require regular liver function
tests and full blood counts. Methotrexate can cause
pneumonitis (inammation of the lung tissue); patients
should report any signicant coughing or shortness of
breath. Acute toxicity is treated with folic acid, and with
hydration and urinary alkalinization to increase the rate
of drug excretion.
Methotrexate has the advantage of a relatively fast onset
of action (about 1 month) compared with many other
DMARDs. Bioavailability is poor in some patients; if an
eect is not seen after 2 months of oral therapy,
subcutaneous administration may be trialled.
9.4.2 Sulfasalazine
Sulfasalazine is a relatively inactive complex of
5-aminosalicylic acid (5-ASA, an anti-inammatory) and
sulfapyridine (a sulfonamide antibiotic). e bond
between the two is cleaved by bacteria in the colon,
releasing the active component parts. e identity of the
active moiety in treating rheumatoid arthritis has been
the subject of much debate. Sulfasalazine has wellestablished antioxidant activity, as a result of scavenging
reactive nitrogen and oxygen species produced by
neutrophils, and this may contribute to its antiinammatory eect. e overall clinical response to
sulfasalazine is likely, though, to result from the collective
eects of 5-ASA, sulfapyridine, and possibly sulfasalazine
itself on a number of additional processes, among which
are:
• modication of lymphocyte proliferation (possibly due
to sulfapyridine’s eect on folate metabolism)
• reduction in pro-inammatory cytokine production
• reduction in eicosanoid production.
Sulfasalazine is frequently the rst-choice DMARD in
mild rheumatoid arthritis. It is eective, cheap, and
convenient (administered orally). It has a shorter lag time
before onset of an eect compared with other DMARDs,
and fewer side eects, the main one being gastrointestinal
disturbance; this is reduced by enteric-coated
preparations, or by taking the drug with food. Other side
eects, including rash and other hypersensitivity
(allergic) reactions, and occasionally bone marrow
suppression (see above), are believed to result from the
action of the sulfapyridine molecule.
9.4.3 Azathioprine
Azathioprine is a pro-drug and undergoes a series of
complicated conversions in the body (Figure 9.6). e
rst step is non-enzymatic conversion to
6-mercaptopurine (a purine analogue), which occurs
largely on the surface of red blood cells. is inhibits DNA
synthesis by competing for the enzymes involved in
purine synthesis. It is also metabolized via 6-thioinosinic
acid, by dierent pathways to yield:
• 6-methyl-mercaptopurine which inhibits purine
biosynthesis
• 6-thioguanine nucleotide which blocks DNA synthesis.
NO
N
N
H3C
Azathioprine 6-mercaptopurine
Figure 9.6 Metabolismofthepro-drugazathioprine.
The first step in the metabolism of azathioprine is a non-enzymatic reduction, which takes place on the surface of red
blood cells (RBC). The 6-mercaptopurine molecule generated is further metabolized to either 6-thioguanine nucleotide
or 6-methyl-mercaptopurine; both have inhibitory effects on DNA synthesis.
2
S
H
N
N
N
RBC
N
S
H
N
N
H
N
N
Thioinosinic acid
6-thioguanine nucleotide
(incorporated into DNA)
6-methyl-mercaptopurine
(inhibits purine synthesis)
226 Chapter 9 Rheumatoid arthritis
Azathioprine inhibits the proliferation of lymphocytes,
including T-cells and B-cells, and has been used for
decades as an immunosuppressant to prevent organ
rejection after transplantation. In the treatment of
rheumatoid arthritis it can take 2–3 months to take eect;
if no response is seen at the maximum tolerated dose
after 6 months, it should be discontinued.
e side-eect prole of azathioprine is worse than that
of methotrexate, with nausea, vomiting, and diarrhoea
being reasonably common. More seriously, the drug can
cause bone marrow suppression and liver toxicity. Some
patients suer toxicity at doses well tolerated by the
majority of patients. is is due to a rare variation in
the gene encoding an enzyme which participates in the
metabolism of thiopurines, and leads to the build-up of
toxic levels of the drug in these patients.
Given the nature and frequency of side eects, use of
azathioprine is generally restricted to patients who have
not responded to other DMARDs.
9.4.4 Ciclosporin
e naturally occurring calcineurin inhibitor ciclosporin
is produced by the fungus Tolypocladium inatum. It is a
potent immunosuppressant which blocks T-cell
activation and the immune response, and is used to
prevent organ rejection following transplantation.
Ciclosporin diuses into cells and binds to a cytosolic
protein called cyclophilin, a member of the
immunophilin family. e drug–immunophilin complex
thus formed binds to and inhibits the enzyme
calcineurin. Calcineurin is a phosphatase, responsible for
the dephosphorylation and activation of transcription
factors in the cytosol belonging to the NFAT family
(nuclear factor of activated T-cells). Inhibition of this
enzyme therefore ensures that NFAT remains
phosphorylated, and in this state is retained in the
cytosol; gene transcription is inhibited. e main action is
an inhibition of the transcription of IL-2, which has a
central role in T-cell proliferation and dierentiation, and
therefore in the development of the immune response
(see Figure P3.2 in the Introduction to Part 3 of this book).
Transcription in T-cells of the genes encoding additional
cytokines, such as interferon-, may also be reduced and
contribute to the potent therapeutic eect of ciclosporin
on the immune system.
Ciclosporin has a narrow therapeutic window and
requires monitoring by serum levels to avoid underdosing
or toxicity. It is associated with a range of serious adverse
eects, including nephrotoxicity, hypertension, liver
toxicity, and bone marrow suppression. Most eects are
dose related, and can be reversed on dose reduction.
Patients must also be regularly monitored for serum
creatinine levels (kidney function), full blood counts, and
liver function tests. Ciclosporin is metabolized in the liver
by the microsomal cytochrome P450 (CYP450) system
(specically, CYP3A4), resulting in a large number of
signicant drug interactions. Amongst these,
corticosteroids and azole antifungal agents (e.g.
ketoconazole) inhibit metabolism, and so increase
ciclosporin levels. e drug should not be taken with
grapefruit juice, which is believed to decrease its
metabolism in the gut wall and augment plasma levels,
sometimes signicantly. Conversely, the anti-epileptic
drugs carbamazepine, phenobarbital, and phenytoin
induce the CYP450 enzymes involved in ciclosporin’s
metabolism; plasma levels are therefore decreased. It is
worth noting that St John’s wort, a popular herbal remedy
for depression, also increases metabolism, and should
not be taken by patients on ciclosporin. e nephrotoxic
eects of ciclosporin are increased by some agents,
including NSAIDs, an interaction of obvious clinical
signicance in the treatment of rheumatoid arthritis,
given that many patients will be using NSAIDs for pain
relief.
e eect of ciclosporin is slow to develop, and may
require several months of treatment before the optimal
response is achieved; it should be discontinued if
ineective after 6 months. Owing to monitoring
requirements and the high incidence of adverse eects,
ciclosporin is generally reserved for severe refractory
rheumatoid arthritis.
9.4.5 Leflunomide
Leunomide blocks DNA and RNA synthesis by inhibiting
dihydro-orotate dehydrogenase, an enzyme involved in
the de novo synthesis of pyrimidines. is inhibits
proliferation, and therefore dierentiation, of T- and
B-cells, resulting in suppression of the immune response.
e drug is given orally, and is converted in the liver into
its active form, teriunomide, which has a long half-life of
around 2 weeks. is is a result of the metabolite’s
secretion into bile, and its being recycled and returned to
the liver alongside bile salts by the enterohepatic
circulation, rather than being excreted in the faeces.
Elimination can be accelerated, for instance in cases of
9.4 Disease-modifying anti-rheumatic drugs (DMARDs) 227
toxicity, by a wash-out procedure using cholestyramine
or activated charcoal. ese molecules bind and
sequester teriunomide in the small intestine and
prevent its reabsorption. In theory the long half-life may
favour use of a loading dose to achieve therapeutic levels
more quickly (see Chapter 3). is is often not followed in
practice, however, due to the likelihood of extreme
gastrointestinal side eects.
Leunomide is hepatotoxic, and regular liver function
tests are recommended. It is a teratogen, and may cause
serious birth defects; it must not be used during
pregnancy, and conception must be avoided for 2 years
after stopping treatment (3 months for men) unless a
wash-out procedure is undertaken (see above). e drug
has also been associated with rare but severe
hypersensitivity skin reactions, such as Stevens–Johnson
syndrome; patients should report any skin changes, such
as the appearance of a rash. e drug’s
immunosuppressive eects mean that patients are at
increased risk of infection, and for this reason should not
receive any live vaccines while being treated and for 6
months after stopping treatment.
Leunomide interacts with many drugs. One of those
aected is the anticoagulant warfarin; its ecacy is
increased, leading to an enhanced risk of bleeding.
Leunomide must be used with caution when combined
with hepatotoxic drugs or other immunomodulatory
agents. It is usually reserved for patients with moderate to
severe refractory rheumatoid arthritis, and is used under
specialist supervision.
(Cyclophosphamide is a further chemotherapy agent
which is occasionally used in the treatment of rheumatoid
arthritis. It interferes with DNA to prevent T- and B-cell
proliferation. It is covered in Chapter 23.)
9.4.6 Gold salts
Gold compounds have been used for centuries in the
treatment of infections, and since 1929 in the treatment of
rheumatoid arthritis. ose currently used in rheumatoid
arthritis are aurothiomalate (given by intramuscular
injection) and auranofin (given orally). e gold salts
gradually accumulate in the synovial joint, although the
way in which they act is far from clear. A large number of
possibilities have been proposed, including:
• inhibition of T-cell activation
• inhibition of neutrophil migration.
Gold compounds are very eective anti-rheumatic drugs.
ey are, though, rarely used because of the frequency
and nature of their side eects. A signicant proportion of
patients are aected, and if therapy is not stopped when
symptoms start to develop, they can become serious. Side
eects result from accumulation of the compounds in
cells and tissues such as the liver, kidney tubules, and
adrenal cortex, where they can persist for long periods.
Both aurothiomalate and auranon can produce
signicant immunosuppression (see above); regular
blood cell counts are necessitated, as is monitoring for
signs of renal dysfunction.
Injections of aurothiomalate can be associated with a
severe vasomotor reaction (fainting, sweating, nausea,
and heart palpitations), requiring patients to lie down for
at least 10 minutes after administration. e most
common side eect of auranon is severe diarrhoea
which can sometimes be treated with bulk-forming
laxatives (e.g. psyllium husks) or a reduction in dose. As
with many other DMARDs, the full anti-inammatory
eect develops slowly over a period of up to 6 months.
9.4.7 Antimalarials
Two antimalarial drugs are used in rheumatoid arthritis:
chloroquine and hydroxychloroquine. As non-polar
compounds, they are readily taken up by cells including
macrophages, and sequestered in intracellular organelles,
such as lysosomes and endosomes, where they increase
the pH. is reduces the processing of antigenic proteins
by macrophages, which requires an acidic environment.
As a consequence T-cell activation, and the ensuing
immune response, are downregulated.
Additional actions of antimalarial drugs have been
proposed, including:
• inhibition of cytokine production by macrophages,
such as IL-1 and TNF-
• inhibition of neutrophil function
• inhibition of macrophage phospholipase A2 activity,
leading to reduced production of inammatory
mediators (eicosanoids).
• inhibition of antigen-processing by resident macrophages
• decreased production of pro-inammatory cytokines
(e.g. IL-1, TNF-)
Both chloroquine and hydroxychloroquine are better
tolerated than many other DMARDs, although they are
not as eective and are generally reserved for mild
228 Chapter 9 Rheumatoid arthritis
disease. eir most common side eects are
gastrointestinal disturbances, skin reactions, dizziness,
and headaches. Rarely, both drugs can cause retinopathy;
patients should have regular eye examinations, and be
encouraged to wear sunglasses to reduce potential
damage. ey also have some quinidine-like eects on
the heart which block voltage-sensitive sodium channels
(see Chapter 7), and can cause changes in the ECG.
e lipophilic nature of the drugs results in extended
half-lives due to accumulation in tissues. Elimination is
consequently slow; the half-life is around 50 days, and
small amounts may persist for many months.
9.4.8 Penicillamine (D-penicillamine)
Penicillamine is a product of penicillin hydrolysis. e
drug is a metal chelator used to treat poisoning with
heavy metals such as mercury and lead. In rheumatoid
arthritis its mechanism of action is unclear, but may
involve a reduction in T-cell proliferation to decrease the
immune response. Penicillamine inhibits crosslinking in
the maturation of collagen, and this may contribute to its
therapeutic eect in diseased joints. Additionally, it has
been postulated that the drug inhibits formation of
immune complexes of rheumatoid factor and
immunoglobulin, central to pathogenesis of rheumatoid
arthritis.
Although penicillamine is an eective DMARD, it is
generally not well tolerated, and gastrointestinal
disturbance, rash, stomatitis, and taste disturbance are
very common. Signicant immunosuppression is,
however, rare, but regular blood tests are still
recommended. Owing to the high incidence of side
eects, penicillamine has only a limited role in the
treatment of rheumatoid arthritis.
9.5 Cytokine blockers: biological DMARDs
e development of biological agents (also called
biologics/biopharmaceuticals) which target specic
aspects of the immune response represents the greatest
advance for many decades in the treatment of chronic
inammatory conditions. Biological agents are
recombinant proteins produced through genetic
engineering. ose used in rheumatoid arthritis either
target the cytokines that play a central role in its
pathogenesis (see Table 9.1), or interfere with activation/
proliferation of T- or B-cells. ey are of two types:
therapy, and must not be given live vaccines during
treatment, as serious infection may result. ey should
also be encouraged to report any signs of bone marrow
suppression (e.g. fever, sore throat, bruising). Infusionrelated hypersensitivity (anaphylaxis) reactions are a risk
with the administration of biological agents. e eects
include hypotension, rash, vomiting, and bronchospasm.
ey can be reduced by the pre-administration of
paracetamol, an antihistamine, and a corticosteroid.
Delayed hypersensitivity reactions are also possible.
1) engineered monoclonal antibodies which neutralize
their target protein (e.g. adalimumab, which targets
tumour necrosis factor-)
2) recombinant engineered proteins (e.g. anakinra, an
engineered copy of the human interleukin-1 receptor
antagonist).
e manufacture of such biological agents is complex,
and they are therefore expensive to produce; those used
in the treatment of rheumatoid arthritis cost hundreds of
times more than some of the older DMARDs. As proteins,
the drugs must be injected, further adding to their
overall cost.
e suppression of the immune system by these agents
leads to an increased risk of infection; biologics must not
be combined as this will further increase the risk. Patients
must be screened for latent tuberculosis before initiating
With all of the above considerations, it is not surprising
that biological agents are generally reserved for use in
patients with very severe rheumatoid arthritis, or who
have not responded to other DMARDs. Biologics are most
commonly used in combination with the older drugs, in
particular methotrexate, where they have been shown to
improve outcomes by 20–50% compared with
methotrexate alone. ey are given under specialist
supervision.
9.5.1 Anti-TNF- agents
Recognition of the central role played in the
immunopathogenesis of rheumatoid arthritis by the
cytokine tumour necrosis factor- (TNF-) has resulted in
the development of a number of biological agents targeting
this protein. ese agents can precipitate or worsen heart
failure and must be used with caution in patients at risk.
9.5 Cytokine blockers: biological DMARDs 229
Etanercept
Etanercept is an engineered fusion protein consisting of
two protein entities each with specic roles.
1. e ligand-binding domain of the TNF receptor
enables the protein to act as a decoy receptor,
providing sites for TNF- to bind, and thereby
removing it from the biologically active pool.
2. A fragment of human immunoglobulin G antibody
increases the molecule’s half-life in plasma (compared
with other proteins in the blood, antibodies have
prolonged lifespans).
Etanercept is given by subcutaneous injection once or
twice a week. Local injection site reactions may develop,
as well as nausea, abdominal pain, fever, and headache
(hypersensitivity reactions; see above).
Infliximab
Iniximab was the rst anti-TNF- agent used in the
treatment of rheumatoid arthritis. It is a monoclonal
antibody against TNF-, a chimera which contains
component parts of both mouse (murine) and human
antibodies. e rationale behind this ‘humanization’ of
the antibody is to reduce the immune response which
would be provoked in patients injected with a purely
murine protein. In addition, the plasma half-life of the
protein is extended (see above). e antibody binds to
circulating TNF- with high anity to neutralize it, and
thereby reduces the immune response.
weekly or every other week for adalimumab, and once a
month for golimumab. Adalimumab can be used as
monotherapy in the treatment of rheumatoid arthritis,
where methotrexate cannot be used.
Certolizumabpegol
Certolizumab is a fragment of an antibody which is
directed against TNF-. e protein molecule is modied
by the addition of polyethylene glycol, which has the
eect of prolonging its half-life. Certolizumab pegol is
given by subcutaneous injection every 2–4 weeks.
9.5.2 Other cytokine blockers
Abatacept
Abatacept is an engineered monoclonal antibody that
inhibits the co-stimulatory signal between the antigenpresenting cell and the T-cell, one of the steps required for
full activation of T-cells (see Figure 9.7 for more detail).
e release of inammatory cytokines is thereby
inhibited, and the immune response suppressed.
Abatacept is given by intravenous infusion every 2 weeks
for three doses, and once a month thereafter. It is used in
Abatacept
CD80/86 CD28
Iniximab is used in combination with methotrexate and
is administered as an intravenous infusion, repeated at 2
and 6 weeks, and thereafter every 8 weeks. e most
common side eects are infusion-related gastrointestinal
disturbances, nasal congestion, headache, and dizziness
(and see above). As the iniximab molecule is part
murine, there remains a risk of the patient developing
antibodies against it, which increases the likelihood of
hypersensitivity reactions.
Adalimumab and golimumab
ese two biologics are ‘fully humanized’ monoclonal
antibodies against TNF-. is means that only a tiny
portion of the molecule, the antigen-binding region,
remains murine in origin, with the remainder being
human. is further reduces the likelihood of
hypersensitivity reactions. Both adalimumab and
golimumab are given by subcutaneous injection, either
Antigen-
presenting
cell
(APC)
MHC Antigen
Figure 9.7 Abatacept blocks the co-stimulatory signal
required for T-cell activation.
The activation of a T-cell requires the presentation of antigenic
peptide, in combination with the major histocompatibility
complex (MHC) molecules on the surface of the antigenpresenting cell. In addition, though, a co-stimulatory signal is
required which involves the interaction between specific proteins
expressed on the T-cell (CD28) and the antigen-presenting cell
(CD80/CD86). Abatacept is an antibody which blocks this
co-stimulatory signal, thereby preventing the activation of T-cells.
T-cell
230 Chapter 9 Rheumatoid arthritis
combination with methotrexate in the treatment of
moderate to severe refractory rheumatoid arthritis, or
where patients are intolerant to other DMARDs. Adverse
eects include injection-site reactions, hypersensitivity,
dizziness, headache, gastrointestinal disturbances, and
an increased risk of infection. As abatacept is a relatively
new agent, long-term safety has not yet been
established.
Tofacitinib
Tofacitinib is the rst of a new class of DMARDs called
jakinibs, which inhibit members of the family of cytosolic
enzymes called Janus kinases (Jak). ese enzymes are
involved in the signal transduction events following the
activation of many cytokine receptors. ey mediate the
response by phosphorylating target proteins inside the
cell. Dierent Jak species are activated by dierent
cytokine receptors. Amongst their target proteins is the
STAT (signal transducer and activator of transcription)
family of transcription factors, which controls many
aspects of cell growth and dierentiation. Jak
phosphorylates and activates STAT proteins, which are
then able to activate gene expression.
Tofacitinib primarily targets Jak1 and Jak3 to block the
actions of a number of cytokines including IL-2 and IL-4,
as well as TNF-, all of which are central to the immune
process in rheumatoid arthritis.
e drug is taken twice a day orally, and is used as
second-line treatment for moderate to severe rheumatoid
arthritis in patients where the response to other DMARDs
is unsatisfactory or where such drugs are not tolerated.
e main side eects are believed to result from Jak-2
inhibition: upper respiratory tract infections, diarrhoea,
nausea and headache, and eects related to suppressed
immune function such as increased risk of infection.
Longer-term studies are needed to assess the potential to
produce cancers through inhibition of the actions of
natural killer cells.
Rituximab
Rituximab targets B-cells, which have a number of key
roles in the immunopathogenesis of rheumatoid arthritis,
including:
• producing rheumatoid factor antibodies
• enabling T-cell activation
• functioning as antigen-presenting cells
• secreting pro-inammatory cytokines, such as TNF-.
Rituximab is a monoclonal antibody directed against a
protein expressed on the surface of B-cells (CD20
protein). e antibody molecules bind to this protein with
a cytotoxic eect, ultimately causing lysis of the B-cells,
and so inhibiting their proliferation (see Chapter 23, Box
23.2, for a detailed account of rituximab’s mechanism of
action). In most patients the population of B-cells
appears to recover around 6 months after treatment,
necessitating repeat therapy.
Rituximab is used in severe rheumatoid arthritis, and
with dierent dosing regimes in a number of B-cell
malignancies, such as chronic lymphocytic leukaemia. In
rheumatoid arthritis it is combined with methotrexate for
patients who have shown intolerance of, or insucient
response to, a number of other DMARDs, including
anti-TNF- agents. Rituximab is administered as two
intravenous infusions, 2 weeks apart, and if necessary
repeated every 6–12 months as the B-cell population
starts to recover.
e main side eects of rituximab are infusion related,
such as fever and rash; taking a combination of
paracetamol, an antihistamine, and methylprednisolone
before administration is recommended to reduce the risk.
Rituximab has been associated with worsening cardiac
conditions such as atrial brillation, and patients at risk
should be monitored closely.
Anakinra
Anakinra is a recombinant form of human interleukin-1
receptor antagonist (IL-1Ra). is is a natural antiinammatory molecule, secreted by monocytes,
macrophages, and neutrophils, which competitively
blocks IL-1 binding at its receptor. Anakinra mimics this
eect, and so modulates the IL-1-mediated inammatory
response. It is given by daily subcutaneous injection. In
rheumatoid arthritis it appears to be less eective
combined with methotrexate than the anti-TNF- drugs,
and for this reason, together with its high cost, is not used
routinely.
Tocilizumab
Tocilizumab is a recombinant humanized monoclonal
antibody that is directed against the interleukin-6 (IL-6)
receptor. IL-6 is a pro-inammatory cytokine, secreted by
T-cells and macrophages, which stimulates B-cell
dierentiation into plasma cells and antibody generation.
It also promotes dierentiation and activation of T-helper
cells, and antagonizes regulatory T-cells. In addition, IL-6
9.6 Choice of treatment for rheumatoid arthritis 231
is secreted by, and stimulates, synovial broblasts
through autocrine action; this contributes to pannus
formation. Osteoclasts are also activated by IL-6, leading
to joint destruction. ese IL-6-mediated eects are
antagonized by tocilizumab, which is administered by
intravenous infusion every 4 weeks.
Table 9.5 summarizes the DMARDs used in the treatment
of rheumatoid arthritis.
Table 9.5 Efcacy, safety, and cost of DMARDs
Drug Route Efficacy Toxicity Monitoring Cost
Hydroxychloroquine Oral
Chloroquine Oral
Sulfasalazine Oral
Penicillamine Oral
Gold salts Oral; IM
Methotrexate Oral; SC
Azathioprine Oral
Ciclosporin Oral
Leflunomide Oral
Abatacept IV
Tofacitinib Oral
Rituximab IV
Etanercept SC
Infliximab IV
Adalimumab SC
Certolizumab SC
Golimumab SC
Anakinra SC
Tocilizumab IV
IM, intramuscular; SC, subcutaneous; IV, intravenous.
BP, blood pressure; FBC, full blood count; LFT, liver function tests; U&E, urea, electrolytes, and creatinine (kidney function).
a
Results in parentheses are the efficacy in combination with methotrexate.
+ +
+ + +
+ + +
+ + + + +
+ + + +
+ + +
+ +
+ + + +
+ + (+ + +)a +
+ + (+ + +) + + + + + +
+ + (+ + +) + + + + +
+ + (+ + +) +/+ + + + + +
+ + (+ + +) +
+ + (+ + +) +/+ +
+ + (+ + +) +
+ + (+ + +) +
+ + (+ + +) +
+ (+ +) +
+ + (+ + +) + +
Retinal examination
Retinal examination
FBC, LFT
FBC, urinalysis
FBC, urinalysis
FBC, LFT, U&E
FBC, LFT, U&E
FBC, LFT, U&E, BP
FBC, LFT, BP, weight
Infections
Infections, hypersensitivity
reaction (anaphylaxis)
Infections
Infections
Infections
Neutrophil count
FBC, LFT, infections, blood lipids
+
+
+
+
+
+
+
+ +
+ +
+ + + +
+ + + +
+ + + +
+ + + +
+ + + +
+ + + +
+ + + +
9.6 Choice of treatment for rheumatoid arthritis
As is obvious from the previous sections, a very large
number of drugs are available for treating rheumatoid
arthritis. Choice will depend on several factors, including
age, gender and occupation of the patient, severity of
disease and previous treatment, cost and side eects of
therapy, and patient preference.
DMARDs should be commenced within 3 months of the
initial diagnosis of rheumatoid arthritis. In mild disease
sulfasalazine is a common rst choice, whereas
methotrexate is usually chosen for moderate or severe
rheumatoid arthritis. Where the response to a single drug
is insucient, a second DMARD can be added. In this
respect, combinations of methotrexate with a number of
other DMARDs, including sulfasalazine, leunomide,
anakinra, or the anti-TNF- biological agents, have been
found to be useful; such combinations can improve the
response to methotrexate alone by 20–40%. All
combinations increase the risk of serious immune
suppression (combinations of anakinra and anti-TNF
agents must be avoided). A general approach to
managing rheumatoid arthritis is outlined in Figure 9.8.