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212 Chapter 9 Rheumatoid arthritis
9.1 What is rheumatoid arthritis?
Rheumatoid arthritis is a chronic inammatory disorder
of the joints. It can, though, aect other organs, thereby
increasing the risk of some serious illnesses, including
cardiovascular disease, lymphomas, and kidney failure.
Initial signs of the disease are pain, stiness, and swelling
of synovial joints, most commonly in the hands and
wrists, although any joints can be aected. Up to a third of
patients report additional symptoms at the onset of the
disease, including muscle pain (myalgia), fatigue, fever,
weight loss, or a general sense of feeling unwell.
Rheumatoid arthritis is more common in females than
males. e onset is usually around 30–50 years, incidence
increasing with age. e disease progresses at variable
rates, but over time there is a loss of function in the aected
joints. e exact cause of rheumatoid arthritis is unclear,
although a combination of genetic, hormonal, and
environmental factors is believed to be involved. Smoking
cigarettes is a strong risk factor. Flares can be triggered by a
variety of conditions, including stress, fatigue, infectious
diseases, and the consumption of certain foodstus.
9.1.1 Pathophysiology of rheumatoid
arthritis
Rheumatoid arthritis is characterized by inammation of
the synovial membrane (or synovium). is is the soft
tissue that lines the brous capsule surrounding the
synovial joint (see Figure 9.1). e synovial membrane
protects and maintains a healthy joint by acting as a
physical barrier to the entry of pathogens, as well as
secreting synovial uid. is uid lls the joint space,
providing a shock-absorbing cushion and lubricating the
ends of the bones, allowing the joint to move freely. e
uid nourishes the underlying hyaline, or articular
cartilage, a smooth and slippery translucent material that
covers the end of the bones, providing an almost
frictionless surface where they meet.
Rheumatoid arthritis is an autoimmune condition where
immune cells inltrate the joint and an inammatory
response is activated inappropriately. A range of cells and
mediators are involved; T-helper cells become activated,
and cooperate in the activation and dierentiation of
Periosteum
Fibrous capsule
Synovial membrane
Hyaline cartilage
Joint cavity containing
synovial uid
Figure 9.1 The anatomy of a synovial joint.
Diagrammatic representation of a synovial joint, indicating the location of
the synovial membrane beneath the outer fibrous capsule surrounding
the joint. This membrane hypertrophies and becomes highly vascularized
and inflamed in rheumatoid arthritis. Erosion of the cartilage and bone
also occurs.
Adapted from Pocock G, Richards C, The Human Body, 2009. By permission of
Oxford University Press.
9.1 What is rheumatoid arthritis? 213
B-cells into plasma cells (see Figure P3.2 in the
Introduction to Part 3 of this book) which generate
antibodies directed against host proteins
(autoantibodies). e autoantibodies, known as
rheumatoid factor (RF), are directed against a further
antibody, immunoglobulin G, with which they form
immune complexes; these are deposited in joints.
Activated T-helper cells have additional roles in the
pathogenesis of rheumatoid arthritis by aecting a range
of cells in the joint including the following.
• Fibroblasts in the synovium which are stimulated to
proliferate, and so increase its thickness. e broblasts
also release destructive enzymes such as collagenases
which destroy the connective tissue in the joint.
• Macrophages are activated, and in turn release
inammatory cytokines, notably interleukin-1 and, in
particular, tissue necrosis factor- (TNF-), which
potentiate the immune response.
• Osteoclasts, the cells in bone responsible for
reabsorbing bone matrix, are stimulated.
• Chondrocytes, or cartilage-producing cells, proliferate,
leading to brosis of the cartilage covering the ends of
the bones.
e proliferative changes generate an increased demand
for oxygen and nutrients, which is met by an increase in
the number of blood vessels (angiogenesis). is further
exacerbates the problem by delivering more
inammatory cells to the aected region. e thickened
synovium migrates across the articular cartilage, lling
the joint space (known as a pannus formation). is
leads to erosion of both cartilage and bone and ultimately
to the degeneration of the joint structure and loss of
movement (ankylosis).
A large number of cytokines drive and coordinate the
overall immune reaction (see Table 9.1) in rheumatoid
arthritis. A dominant role is played by TNF- released by
macrophages and other immune cells; not surprisingly,
this key inammatory regulator is the target of a number
of therapeutically eective drugs (see Section 9.5.1). e
steps in the immune process are the subject of Box 9.1.
Also central to the process of inammation in joints aected
by rheumatoid arthritis are prostanoids, a group of
mediators encompassing prostaglandins and thromboxane
A2 (Figure 9.2). Together with leukotrienes, they are the
principal eicosanoids: a class of short-lived local mediators
which alter the activities of the cell in which they are
generated (autocrine action), as well as cells nearby
(paracrine action). Eicosanoids are involved in the control of
many physiological processes including, crucially, the
inammatory response. As you will see below, this makes
them very important drug targets. (e eicosanoids are
considered further in the Introduction to Part 3 of this book.)
Because of their lipophilic nature these eicosanoid
mediators cannot be stored pre-formed in cells, but are
generated as required. e precursor for eicosanoids is
arachidonic acid, a fatty acid present in all cells as a
constituent of phospholipids in plasma and intracellular
membranes (e.g. the nuclear membrane). e rst step in
the conversion of arachidonic acid into prostanoids is
catalysed by the enzyme cyclo-oxygenase (COX). is
enzyme is the target for one of the most widely used drug
Table 9.1 Roles and sources of some key cytokines in the pathogenesis of rheumatoid arthritis
Cytokine Sources Effect
IL-1 Macrophages, T-cells Stimulation of cytokine and prostaglandin synthesis, and collagenase activity
Activation of fibroblasts and osteoclasts
IL-2 T-cells Stimulates the proliferation and activation of T, B, and natural killer cells
IL-4 Th2 cells Promotes differentiation and proliferation of Th2 cells
IL-6 Macrophages, T-cells, synovial
fibroblasts
RANKL T-helper cells Osteoclast differentiation and activation
TNF-
IL, interleukin; TNF-, tumour necrosis factor-; RANKL, receptor activator of nuclear factor B ligand; Th2, T-helper 2 cells.
Macrophages Stimulation of cytokine and prostaglandin synthesis, and collagenase activity
Maturation of B-cells
Antagonizes regulatory T-cells
Mediator of fever
Activation of fibroblasts and osteoclasts
Kills tumour cells
Box 9.1
Immunopathogenesis of rheumatoid arthritis
1 Type A synoviocyte
2 Type B synoviocyte
Blood vessel
p
3
A
P
C
Figure a
1 Type A synoviocytes are resident macrophages that phagocytose invading pathogens.
2 Type B synoviocytes are fibroblast-like cells that produce synovial fluid and collagen.
3 Type A synoviocytes act as antigen-presenting cells to activate T-helper cells. T-helper 2 cells cooperate in the
activation and differentiation of B-cells into plasma cells. Activated T-cells produce a number of cytokines including
the interleukins IL-2 and IL-4, as well as interferon ; these cytokines stimulate both type A and B synoviocytes. The
T-cells also express a cytokine central to bone remodelling: receptor activator of nuclear factor B ligand (RANKL).
4 Plasma cells produce autoantibodies (rheumatoid factor).
5 The activated macrophages (type A cells) produce IL-l and tumour necrosis factor (TNF-). These cytokines
stimulate osteoclasts and fibroblasts (type B cells), as well as promoting the release of other cytokines and
chemokines.
6 The fibroblasts produce enzymes such as collagenase and elastase, which destroy connective tissue in the joint.
7 Rheumatoid factor binds immunoglobulin G to form an immune complex that is deposited in the joint.
8 RANKL, expressed by activated T-helper cells, binds to its receptor on osteoclasts, thereby activating the
transcription factor, nuclear factor B. This promotes the differentiation and activation of osteoclasts, which reabsorb
the mineralized matrix of bone, leading to its erosion. Osteoclasts are also activated by other cytokines such as IL-6
released from type B synoviocytes.
T
= T-cell; P = plasma cell; Y = rheumatoid factor; Y = immunoglobulin G; APC = antigen-presenting cell.
T
Osteoclast
p
p
p
p
p
4
6
5
7
5
8
Healthy joint
Rheumatoid arthritis joint
9.1 What is rheumatoid arthritis? 215
Phospholipids in cell membranes
Phospholipase A
2
Arachidonic acid
Cyclo-oxygenase
PG1
2
TXA
2
PGD
2
PGE
2
PGF
2
Blood vessels Platelet aggregation Nociceptors
(pain receptors)
Figure 9.2 Generation of prostanoids, and their roles in the inflammatory response.
Phospholipids in cellular membranes are cleaved by phospholipase A2 to generate arachidonic acid, the precursor
for both prostanoids and leukotrienes. Cyclo-oxygenase mediates the first step in the conversion of arachidonic
acid, via a group of unstable cyclic endoperoxides, to generate the prostanoids: thromboxane A2 and the
prostaglandins.
, decreases/constricts; , increases/dilates; PGI2, prostaglandin I2 (prostacyclin); TXA2, thromboxane A2; PGD2, prostaglandin D2;
PGE2, prostaglandin E2; PGF2, prostaglandin F2.
classes, non-steroidal anti-inammatory drugs (NSAIDs),
which inhibit its action.
COX-1 and COX-2
Two main isoforms of the enzyme exist: COX-1 and
COX-2 (other isoforms have been postulated but, as yet,
not characterized). COX-1 is present in most cells as a
constitutive enzyme (i.e. one that is continuously
expressed). e prostanoids generated have numerous
crucial roles, including preservation of the integrity of the
gastric mucosa, maintaining renal blood ow by dilating
aerent arterioles, and inhibiting thrombus formation at
the endothelium.
COX-2 is not normally present at signicant levels in most
cells, except those in the kidney, but its expression is
strongly induced by inammatory cytokines, including
interleukin-1 and TNF-, released by macrophages
during the inammatory process in rheumatoid arthritis.
e prostanoids generated by COX-2 activity are therefore
those believed to be responsible for furthering this
autoimmune reaction. e major species are
prostaglandin E2 (PGE2) and prostacyclin (PGI2). eir
eects, which are mediated by G-protein-coupled
receptors, include:
• direct vasodilatation, and potentiation of the eects of
other local vasodilators, such as bradykinin and
histamine, which results in increased blood ow and
redness in the aected area
• potentiation of the eects of bradykinin and histamine
on vascular permeability, leading to oedema and
swelling
• sensitization of nociceptors (receptors for pain),
enhancing the sensation of pain (see Chapter 20,
Section 20.1.1)
• Resetting the body’s thermostat in the hypothalamus,
leading to fever (pyrogenic).
216 Chapter 9 Rheumatoid arthritis
9.1.2 Diagnosing rheumatoid arthritis
Diagnosis of rheumatoid arthritis is based on a
combination of symptoms, patient history, and the results
from a number of investigations. Rheumatoid factor is
detected in routine testing in around 80% of patients with
rheumatoid arthritis, but its use in diagnosing the
condition is limited by the following observations:
• levels are not always elevated in early disease
• approximately 5% of healthy subjects have raised levels
• raised levels are seen in a number of other disease
states such as hepatitis and viral infections, and in
patients with systemic lupus erythematosus (another
autoimmune disease similar to rheumatoid arthritis,
but aecting a range of tissues other than joints).
Detection of rheumatoid factor can, however, be useful in
diagnosing rheumatoid arthritis in conjunction with
other investigations (e.g. markers of inammation such as
abnormal C-reactive protein (CRP) or erythrocyte
sedimentation rate), the nature and duration of
presenting symptoms, and family history. Diagnosis of
rheumatoid arthritis is explored in Workbook 6 when our
ctional patient Pamela is rst diagnosed with the
disease.
9.2 Treatment of rheumatoid arthritis
e damage to the structure of joints in rheumatoid
arthritis is largely irreversible and starts early in the
disease process. is necessitates early and aggressive
intervention with drugs to minimize further joint damage,
and to maintain or improve quality of life. e ultimate
aim of therapy is to achieve disease remission—reduced
signs and symptoms of disease activity. Rheumatoid
arthritis is managed not only through pharmacological
means, and a multidisciplinary team of health care
professionals should be involved. e individual needs of
a patient must be assessed in order to direct support
appropriately, and this is most likely to involve a number
of areas (e.g. physiotherapy, psychological support, and
occupational therapy).
e pharmacological agents used to treat rheumatoid
arthritis are broadly classied into anti-inammatory
drugs, disease-modifying anti-rheumatic drugs
(DMARDs), and the newest class of drugs—biological
agents which target specic mediators involved in the
disease process.
9.2.1 First-line therapy—DMARDs or
anti-inflammatories?
Anti-inammatory drugs, particularly NSAIDs, were for
many years considered as rst-line early treatment for
rheumatoid arthritis. It is now evident that early
treatment with DMARDs, to tackle the underlying disease
process, yields a much better outcome; NSAIDs and
corticosteroids, which treat only symptoms, are reserved
for pain management (NSAIDs) and acute ares
(corticosteroids). Anti-inammatory drugs are also useful
whilst awaiting conrmation of diagnosis, and in the
period before the therapeutic response to DMARDs has
developed fully, which can take several months.
9.3 Anti-inflammatory drugs
Anti-inammatory drugs have a signicant role in the
treatment of rheumatoid arthritis. Two main classes of
drugs are used: non-steroidal anti-inammatory drugs
and corticosteroids.
9.3.1 Non-steroidal anti-inflammatory
drugs (NSAIDs)
e NSAID class includes a wide range of drugs with
dierent chemical structures, but with similar therapeutic
eects including:
• antipyretic (reducing fever)
• analgesic (reducing pain)
• anti-inammatory.
ese eects all result from inhibition of the enzyme
cyclo-oxygenase (COX), and the consequent reduction in
prostanoid generation. NSAIDs are crucial for the
management of pain and swelling of aected joints in
rheumatoid arthritis. Pain relief starts soon after the rst
dose, with the full eect normally seen within a week; the
anti-inammatory response can take 3 weeks to develop.
As noted earlier, two isoforms of COX have been
identied and characterized. It is the COX-2 isoform that
9.3 Anti-inflammatory drugs 217
Ibuprofen Celecoxib
is believed to generate the prostanoids implicated in the
inammatory response. e older NSAIDs are nonselective, inhibiting both COX-1 and COX-2; their
anti-inammatory eects are therefore assumed to derive
from COX-2 inhibition, while the most common adverse
eects on the gastrointestinal tract are thought to arise
from inhibition of COX-1. ere are a great number of
non-selective NSAIDs, including ibuprofen, diclofenac,
ketoprofen, and naproxen.
Attempts to develop NSAIDs with reduced
gastrointestinal eects have led to the introduction of
COX-2 selective agents: the ‘coxibs’. Selectivity exploits
dierence in structure of the binding sites of the two
isoforms of the enzyme; COX-2 can accommodate bulkier
molecules which are unable to access the narrower
COX-1 site whose structure limits interaction to relatively
small chemical structures (Figure 9.3).
Examples of coxibs are celecoxib, parecoxib, and the
highly selective etoricoxib. Some drugs display moderate
selectivity, such as meloxicam; at low dose it is selective
for COX-2, while at high dose it behaves as a non-selective
NSAID.
H
2
HO
O
COX-1 receptor
Figure 9.3 Differences in structure of the binding sites
of the two cyclo-oxygenase (COX) isoforms.
The binding site of COX-1 is a narrow channel, whereas that of
COX-2 has a bulkier side pocket. These differences determine
the chemical structures which can gain access to the binding
site to interfere with enzyme activity. The narrow form of
ibuprofen enables this drug to enter either binding site; it is a
non-selective COX inhibitor. In contrast, the bulkier structure of
celecoxib prevents it gaining access to the binding site of
COX-1, whilst still fitting into that of COX-2; it is COX-2 selective.
N
S
O
O
COX-2 receptor
e various NSAIDs have similar ecacies, but there is
patient variation in both the response and tolerance to
any given agent. Drugs dier in terms of required
frequency of dosing, routes of administration, and side
eects; choice needs to take into account the individual’s
risk factors, in particular age.
NSAIDs are generally taken orally. Some drugs are also
available as suppositories (e.g. indometacin, ketoprofen,
and diclofenac) or for parenteral administration
(ketorolac and parecoxib); both forms are useful for
patients unable to swallow. Many NSAIDs are also
available in topical formulations which have the
advantage of reduced systemic side eects, although
evidence for the ecacy of such preparations in
rheumatoid arthritis is so far limited. Topically applied
NSAIDs can, however, be useful in other musculoskeletal
inammatory conditions (e.g. sprains, strains, and soft
tissue injuries).
Unwanted effects of NSAIDs, and drug combinations
to avoid
When used to treat rheumatoid arthritis, NSAIDs are
taken over prolonged periods often at high dose,
increasing the patient’s risk of side eects, in particular
gastrointestinal toxicity, which is extremely common and
can be serious. is mainly arises from inhibition of
COX-1 in the gastric mucosa where prostanoids play a
F
N
F
N
F
protective role; it is less of a problem with COX-2 selective
NSAIDs. Gastrointestinal symptoms commonly include
discomfort, nausea, and diarrhoea, but sometimes also
ulceration and gastric bleeding. All NSAIDs, including
coxibs, are contraindicated in patients with active ulcers
or gastrointestinal bleeding. e risk of this type of side
eect varies amongst the non-selective NSAIDs; it is
lowest with ibuprofen, and greatest with ketoprofen,
ketorolac, and piroxicam. e gastric mucosa can be
protected against the damaging eects of NSAIDs by
concurrent therapy with a proton pump inhibitor (e.g.
lansoprazole) to reduce acidity in the stomach (see
Chapter 12, Section 12.2.1). Alternatively, the risk of
gastrointestinal tract damage can be mitigated by the
co-administration of a synthetic prostaglandin analogue
(e.g. misoprostol); diclofenac and naproxen are both
available in preparations combined with this drug.
Aspirin is a non-selective NSAID. Although it is now
rarely given for its anti-inammatory properties, it is
widely used as an antiplatelet drug. Unlike other NSAIDs,
aspirin inactivates COX-1 by irreversible acetylation. is
218 Chapter 9 Rheumatoid arthritis
particularly aects platelets since they are anuclear, and
cannot overcome the inhibition, as other cells can, by
synthesizing more COX-1 protein. e inhibition of
COX-mediated synthesis of pro-aggregatory
thromboxane explains the common use of low dose
aspirin as an antiplatelet drug (see Section 4.2.2). is
raises a number of points of concern.
1. Aspirin can cause a potentially hazardous potentiation
of the eect of warfarin, thereby increasing the risk of
bleeding. is is due, at least in part, to the
displacement of protein-bound warfarin as well as the
combined actions of the two drugs on the haemostatic
process (Chapter 4). Extreme care should be exercised
when any NSAID is given to patients on warfarin, and
in particular the elderly.
2. e combination of low dose aspirin (as an
antiplatelet) with another non-selective NSAID
increases the risk of adverse gastrointestinal eects,
and should be avoided wherever possible.
3. NSAIDs, and in particular ibuprofen, have been shown
to protect platelet COX enzyme from irreversible
acetylation by aspirin, presumably by blocking its
access to the COX active site. e antiplatelet eect of
aspirin will thereby be reduced.
In asthmatic patients, NSAIDs, particularly aspirin, can
precipitate bronchospasm (termed aspirin-sensitive
asthma) and should be used with caution.
e major products of COX-2 activity, PGE2 and PGI2,
have important roles in the kidneys, promoting Na+ (and
hence water) excretion, and maintaining renal blood
ow by causing vasodilatation of the renal arterioles.
NSAIDs inhibit these eects and will therefore worsen
renal impairment. (is has even been reported
following use of topical NSAIDs.) e risk of renal failure
is increased as a result of the potentially serious
interaction between NSAIDs and the antihypertensive
ACE inhibitors/angiotensin II receptor antagonists (see
Chapter 5, Section 5.2.1). e risk is heightened still
further with the concomitant use of diuretics (sometimes
called the triple whammy). is is of particular concern
given that NSAIDs are available as non-prescription
drugs, and that ACE inhibitors/angiotensin II receptor
antagonists and diuretics are often prescribed together
for hypertension. (It is also worth noting that the
antihypertensive eect of these drugs is counteracted by
NSAIDs, which themselves cause an increase in arterial
blood pressure.)
By inhibiting the biosynthesis of PGE2 and PGI2, NSAIDs
can precipitate or aggravate heart failure (see Chapter 7)
through multiple mechanisms including:
• reduction of the vasodilatory inuence of PGE2 and
PGI2 on the renal arterioles, which decreases the rate of
ltration in the kidneys, decreasing urine output
• reduction of Na
prostanoids, which leads to Na+, and hence also uid,
being retained.
Both eects exacerbate the condition by increasing the
volume of blood which the failing heart has to pump
around the body (see Chapter 7, Section 7.4).
e renal eects of NSAIDs can also aggravate a number
of other conditions, including cirrhosis of the liver.
NSAIDs carry a dose-dependent risk of cardiovascular
events such as stroke or myocardial infarction, greatest
for the COX-2 selective coxib drugs and for high dose
diclofenac (150 mg daily) and ibuprofen (2.4 g daily). e
exact mechanism behind this eect is not clear, but is
likely to be related to the ability of these drugs to increase
arterial blood pressure. It has been postulated that
NSAIDs promote a prothrombotic state by dierentially
aecting the balance of prostanoid generation. In this
scheme, the production of antithrombotic prostacyclin
(PGI2) by the endothelium is inhibited more profoundly
by NSAIDs than the synthesis of prothrombotic
thromboxane. e diminished antithrombotic inuence
of the vascular endothelium tips the balance in favour of
recruitment of platelets into a thrombus (see Chapter 4,
Section 4.2.2, for details of these processes).
Choice of NSAID
When choosing an NSAID, the main considerations are
the individual’s risk of gastrointestinal complications and
CV events (see Table 9.2). Selection must take into
account existing and previous medical conditions (e.g.
peptic ulcers, gastro-oesophageal reux, angina, previous
myocardial infarction). Where gastrointestinal risk is
high, a COX-2 selective agent is preferred. Where this risk
is low, it is not cost eective to use these drugs, and the
older non-selective NSAIDs are more appropriate.
Adverse lifestyle factors, such as obesity, smoking, and
type II diabetes, must also be considered.
It should be noted that rheumatoid arthritis is a chronic
condition, often necessitating long-term administration
of high dose NSAIDs. e risk of all side eects is both
+
excretion normally promoted by these
9.3 Anti-inflammatory drugs 219
Table 9.2 Selection of non-steroidal anti-inammatory drug (NSAID) based on gastrointestinal and cardiovascular risk
Cardiovascular (CV) risk
Gastrointestinal risk
Low Non-selective NSAID
High COX-2 selective NSAID Non-selective NSAID plus a proton pump
Low High
Non-selective NSAID
(Ibuprofen has lowest GI risk)
Avoid diclofenac (increased CV risk) and
ibuprofen (blocks effect of low dose aspirin)
Current best choice: naproxen
inhibitor (see Chapter 12)
Avoid diclofenac and ibuprofen (as above)
Current best choice: naproxen
dose and time dependent, and so drugs should always
be prescribed at the lowest eective dose for the
shortest possible period. It is also worth remembering
that the incidence of rheumatoid arthritis increases
with age, as does the likelihood of adverse eects of
NSAIDs.
9.3.2 Corticosteroids
Corticosteroid drugs mimic the actions of steroids
produced by the adrenal glands which sit above each of
the kidneys. e secretions from these glands are
essential for life: catecholamines (from the medulla) and
steroids (from the cortex, hence corticosteroids). e
corticosteroids are of two types:
1) mineralocorticoids, which aect water and electrolyte
balance
2) glucocorticoids which have anti-inammatory actions,
as well as wide-ranging eects on metabolism of
carbohydrate, protein, and fat.
e main endogenous mineralocorticoid is aldosterone,
which aects sodium and water reabsorption in the
kidney. It is a component of the renin–angiotensin–
aldosterone system (RAAS), which regulates plasma
volume and vascular tone, and is a target for drugs used
in hypertension (Chapter 5) and heart failure (Chapter 7).
Receptors for aldosterone are limited in distribution to
key areas involved in Na+ excretion, such as the kidney
and colon.
A number of glucocorticoids are produced by the adrenal
glands, the main one being hydrocortisone (also called
cortisol). Glucocorticoid receptors are present in most
cell types, and regulate many aspects of metabolism.
Crucial to their importance as drug targets, these
receptors also mediate anti-inammatory
immunosuppressive eects.
Naturally occurring corticosteroids have both
mineralocorticoid and glucocorticoid actions. is is also
true of many of the synthetic drugs, although a number
have been successfully developed with predominantly
glucocorticoid anti-inammatory activity (e.g.
betamethasone and triamcinolone). It is worth noting
that when referring to drugs, the terms corticosteroid and
glucocorticoid are often used interchangeably.
The hypothalamic–pituitary–adrenal axis
Release of the adrenal steroid hormones is controlled by
adrenocorticotrophic hormone (ACTH), secreted by the
anterior pituitary gland. e release of ACTH is in turn
regulated by corticotrophin-releasing factor (CRF)
secreted by the hypothalamus. is interrelationship is
referred to as the hypothalamic–pituitary–adrenal axis
(HPA axis). Secretion of ACTH, and hence cortisol, has a
circadian rhythm, peaking in the morning and declining
to a low point in the night. It is also stimulated by
conditions such as stress, pain, and fever. e presence of
increasing concentrations of corticosteroids in the blood
inhibits the release of both ACTH and CRF, via negative
feedback loops, as outlined in Figure 9.4.
As a consequence of the negative feedback, the
appearance of administered glucocorticoids in the blood
suppresses the HPA axis. Prolonged therapy can cause the
adrenal gland to atrophy (shrink). It is slow to recover its
corticosteroid-synthesizing capacity, and insuciency
can persist for more than a year after stopping treatment.
is presents a potentially dangerous situation if drugs
were to be withdrawn suddenly after prolonged therapy
(see below).
Suppression of the immune response
Glucocorticoids are the most powerful anti-inammatory
agents, and are employed to suppress the immune
220 Chapter 9 Rheumatoid arthritis
Hypothalamus
CRF
Pituitary
ACTH
Adrenal
gland
Glucocorticoids Mineralocorticoids
Figure 9.4 Control of corticosteroid secretion from the
adrenal gland.
The dotted lines show the negative feedback loops from
glucocorticoids detected in the blood to inhibition of secretion of
CRF from the hypothalamus, and of ACTH from the anterior
pituitary. CRF, corticotrophin-releasing factor; ACTH,
adrenocorticotrophic hormone.
response in rheumatoid arthritis and other inammatory
conditions. e accompanying eects on the metabolism
of carbohydrates, fats, and protein are unwanted side
eects (see Table 9.3).
Corticosteroids in the treatment of rheumatoid
arthritis
In rheumatoid arthritis, corticosteroids are administered
orally and as intra-articular injections (directly into the
joint). A number of drugs are used which dier in terms of
their relative potency as indicated in Table 9.4, which
additionally shows their usual route of administration.
Table 9.4 Potencies of corticosteroids commonly used in
rheumatoid arthritis relative to hydrocortisone
Corticosteroid Relative
potency
Hydrocortisone 1
Prednisolone 4
Prednisone 4
Triamcinolone 5
Betamethasone 25
Methylprednisolone 5
Oral Intra-
articular
✓
✓
✓
✓
✓
✓
e most common oral corticosteroids are the related
drugs prednisolone and prednisone. Prednisone is
inactive until modied to prednisolone in the body; the
two compounds appear to undergo complex reversible
metabolism to each other in the liver. e equivalent oral
dose is therefore the same. Oral corticosteroids are
usually given in the morning so as to mimic the normal
circadian release of corticosteroids by the adrenal gland.
Intra-articular steroids have the advantage of reduced
systemic side eects and less HPA suppression (see
Table 9.3 The therapeutic and adverse effects (in red) of corticosteroids
Glucocorticoid effects on:
Immune response
Carbohydrate metabolism
Protein metabolism
Fat metabolism
Calcium regulation Decrease in absorption from GI tract, and increase in renal excretion
Mineralocorticoid effects on:
Kidney
Inhibition of the immune response susceptibility to infection, impaired wound healing
Reduction in uptake of glucose, and increase in gluconeogenesis hyperglycaemia,
predisposing to diabetes
Decrease in synthesis, and increase in breakdown of proteins muscle wasting and thinning
of skin
Promotion of lipolysis redistribution of fat (‘buffalo hump’ and ‘moon face’)
Increase in number of osteoclasts osteoporosis
Increase in sodium reabsorption and excretion of potassium sodium and water retention
(hypertension, oedema), hypokalaemia (arrhythmias)
9.4 Disease-modifying anti-rheumatic drugs (DMARDs) 221
below), but this method of administering the drug is only
practical when a few joints are aected, and then only for
a limited time.
e main side eects of long-term oral corticosteroid use
are outlined in Table 9.3. Given their metabolic eects,
patients may need to have blood glucose levels and bone
mineral density monitored. Although the exact
mechanism is not understood, corticosteroids are known
to cause an increase in intraocular pressure, which can
progress to glaucoma and loss of sight. Cataracts are also
a risk with long-term therapy.
e immune-suppressing eects may mean that patients
have an increased risk of infection, and wounds may heal
more slowly. Corticosteroids can also aect mood, and
produce depression or psychotic symptoms. As discussed
above, a serious adverse outcome of oral steroid therapy
is suppression of the HPA axis (see Figure 9.4). Stopping
these drugs abruptly after prolonged treatment can give
rise to serious, and potentially fatal, adrenal insuciency,
sometimes called an ‘Addisonian crisis’ as symptoms
resemble those of Addison’s disease: muscle weakness,
hypotension, depression, weight loss, and
hypoglycaemia. It is recommended that patients who
have received prolonged therapy with high doses of
corticosteroids (>20 mg prednisolone/day (or equivalent)
for >3 weeks) should have drugs withdrawn slowly; the
rate of tapering depends on the duration of treatment and
dose of the corticosteroid.
Corticosteroids inhibit transcription of the gene encoding
COX-2 (see Box 9.2), and when combined with aspirin
they can increase the risk of gastrointestinal bleeding and
peptic ulcers.
Because of their potent immunosuppressive eects, the
wide range of potentially serious side eects, and the
possible suppression of the HPA axis, oral corticosteroids
are generally reserved for severe are-ups of rheumatoid
arthritis. As in all applications of these drugs, the least
potent drug should be used for the shortest period possible.
9.4 Disease-modifying anti-rheumatic drugs (DMARDs)
DMARDs are a heterogeneous group of agents that
suppress the immune response in rheumatoid arthritis
using a variety of dierent modes of action, not all of
which are understood (Figure 9.5). ey are rst-line
agents in the treatment of moderate to severe disease,
and should be commenced within 3 months of
diagnosis.
A number of DMARDs, including methotrexate, were
originally designed for, and are still used in, cancer
therapy. In the treatment of rheumatoid arthritis they are
taken at much lower dose (typically 100–1000-fold lower)
to target the rapid cell division and inammatory
response central to the disease. It is important to note that
DMARDs have a limited eect on the pain associated with
rheumatoid arthritis; patients often require the addition
of an NSAID for pain relief. Not surprisingly, bone
marrow suppression is a risk associated with many
DMARDs, leading to reduced levels of leucocytes and
platelets (also produced in the bone marrow). A
decreased number of neutrophils (neutropenia) is a
particular risk, leaving the patient susceptible to
infection. Patients should be encouraged to report any
unexpected bleeding and bruising (due to decreased
levels of platelets), and signs of infection (e.g. fever, sore
throat, or mouth ulcers).
9.4.1 Methotrexate
Methotrexate is considered to be one of the most
eective DMARDs available. It is an analogue of folic acid
and inhibits the enzyme dihydrofolate reductase (DHFR)
in cells. DHFR converts dihydrofolic acid to
tetrahydrofolic acid, which is required as a cofactor for
DNA synthesis. Inhibition of this reaction specically
blocks production of thymidylate: the thymine-basecontaining nucleotide, one of the precursors for DNA
synthesis. is antiproliferative action of methotrexate is
the basis of the drug’s use at high dose in cancer, to inhibit
rapidly dividing cells (Chapter 23). is mechanism,
however, does not appear to underlie its action in
rheumatoid arthritis, as folic acid supplementation does
not alter its eectiveness. (is regime does, though,
reduce side eects; see below.)
A number of methotrexate’s immunosuppressive actions
are believed to be a consequence of the drug’s ability to
increase the production and release of adenosine. is is
a short-lived anti-inammatory molecule, which acts
locally by activating G-protein-coupled receptors.
Stimulation specically of the Gs-coupled A2A receptor
subtype is implicated in the anti-inammatory eect, and
is believed to mediate many of methotrexate’s benecial