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232 Chapter 9 Rheumatoid arthritis
Initial diagnosis of rheumatoid arthritis
• Start non-biological DMARD within 3 months
• Consider NSAIDs for pain
• Consider corticosteroids if moderate/severe
• Provide patient education and
physical/occupational therapy
Satisfactory response?
YES
Monitor
disease
progression
NO
• Change non-biological DMARD
• Add second non-biological DMARD
Satisfactory response?
NO
YES
• Add biological DMARD
(anti-TNF-α agent)
Satisfactory response?
NO
YES
• Change biological DMARD
(alternative anti-TNF-α
agent or rituximab)
Figure 9.8 Algorithm for treating rheumatoid arthritis.
DMARD, disease-modifying anti-rheumatic drug; NSAIDs, non-steroidal anti-inflammatory drugs.
9.6 Choice of treatment for rheumatoid arthritis 233
Key references and suggested reading
Chan ESL, Cronstein BN. Molecular action of methotrexate in
inammatory diseases. Arthritis Res 2002; 4(4): 266–73.
Kean WF, Kean IR. Clinical pharmacology of gold.
Inammopharmacology 2008; 16: 112–25.
Kubler P. Janus kinase inhibitors: mechanisms of action. Aust
Prescr 2014; 37: 154–57.
Lee ATY, Pile K. Disease modifying drugs in adult rheumatoid
arthritis. Aust Prescr 2003; 26: 36–40.
NICE. Rheumatoid arthritis: the management of rheumatoid
arthritis in adults. National Institute for Health and Care
Excellence Clinical Guidelines CG79, 2009. http://www.nice.
org.uk/Guidance/CG79.
Nielsen OH, Ainsworth M, Csillag C, Rask-Madsen J. Systematic
review: coxibs, non-steroidal anti-inammatory drugs or no
cyclooxygenase inhibitors in gastroenterological high-risk
patients? Aliment Pharmacol er 2006; 23: 27–33.
Olsen NJ, Stein CM. New drugs for rheumatoid arthritis. New
Engl J Med 2004; 350: 2167–79.
O’Shea JJ, Kontzias A, Yamaoka K, Tanaka Y, Laurence A. Janus
kinase inhibitors in autoimmune diseases. Ann Rheum Dis
2013; 72(Suppl 2): ii111–15.
Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR,
et al. American College of Rheumatology 2008
recommendations for the use of nonbiologic and biologic
disease-modifying antirheumatic drugs in rheumatoid
arthritis. Arthritis Rheum 2008; 59: 762–84.
SUMMARY OF DRUGS USED FOR RHEUMATOID ARTHRITIS
Therapeutic class Drugs Mechanism of action Common clinical uses Comments Common adverse drug reactions
NSAIDs Non-selective COX
Corticosteroids Dexamethasone
Disease-modifying
anti-rheumatic drugs
(DMARDs)
inhibitors
Examples include:
Aspirin
Diclofenac
Ibuprofen
Indometacin
Ketoprofen
Naproxen
COX 2 selective inhibitors:
Celecoxib
Etoricoxib
Meloxicam
Parecoxib
Hydrocortisone
Methylprednisolone
Prednisolone
Triamcinolone
Methotrexate Mechanism of action
Inhibit COX to reduce
synthesis of
prostaglandins and
thromboxane A
Act through nuclear
receptors to induce or
repress the transcription
of target genes, ultimately
leading to antiinflammatory effects
unclear
Thought to increase
extracellular adenosine, a
local anti-inflammatory
agent which inhibits
cytokines, such as IL-2
and TNF
Inhibition of IL-1 also
postulated, and increased
levels of inhibitory cytokine
IL-10
2
Rheumatoid arthritis
Osteoarthritis
Acute gout
Inflammatory pain and tissue
injury
Fever
Rheumatoid arthritis and
other autoimmune diseases
Allergies
Asthma
Neoplastic diseases
Rheumatoid arthritis
Cancer therapy
Psoriasis
COX-2 selective inhibitors and
diclofenac associated with
increased risk of CV events
Usually reserved for secondline use in rheumatoid arthritis
Some drugs can be injected
directly into joints
Side effects dependent on
dose, duration, and route of
administration
Taken once weekly
Folic acid supplementation
reduces side effects
Anti-inflammatory action differs
from cytotoxic action in cancer
therapy
Monitoring required
Nausea
Diarrhoea
Bleeding
Ulceration
Hypersensitivity (allergic) reactions (rash,
angioedema, bronchospasm)
Increased susceptibility to infection
Delayed wound healing
Hyperglycaemia
Fat redistribution (e.g. moon face)
Osteoporosis
Dyspepsia (indigestion)
Skin thinning
Oedema
Hypertension
Growth retardation in children
Weight gain
Amenorrhoea
Psychiatric disturbances
Pneumonitis
Stomatitis
Nausea
Diarrhoea
Bone marrow suppression
234 Chapter 9 Rheumatoid arthritis
9.6 Choice of treatment for rheumatoid arthritis 235
Sulfasalazine Mechanism unclear
Azathioprine Pro-drug for
Ciclosporin Inhibits calcineurin to
Leflunomide Blocks DNA synthesis by
Gold compounds:
Aurothiomalate
Auranofin
Scavenges reactive
oxygen and nitrogen
species released by
neutrophils, to limit
damage
Also possibly reduces
lymphocyte proliferation,
and synthesis of cytokines
and eicosanoids
6-mercaptopurine, a
purine analogue which
blocks synthesis of purine
precursors for RNA and
DNA
Inhibits lymphocyte
proliferation
block transcription of
genes for IL-2 and other
cytokines
Decreases proliferation
and differentiation of
T-cells
inhibiting production of
pyrimidines
Inhibits T- and B-cell
proliferation, and
suppresses immune
response
Mechanism unclear
Possible inhibition of:
1) antigen-processing by
resident macrophages
2) decreased production
of pro-inflammatory
cytokines
3) inhibition of T-cell
activation and of
neutrophil migration
Rheumatoid arthritis
Inflammatory bowel disease
Autoimmune diseases
including rheumatoid arthritis
Prophylaxis of transplant
rejection
Severe rheumatoid arthritis
Autoimmune diseases
Prevention of transplant
rejection
Severe eczema and
psoriasis
Rheumatoid arthritis Metabolized by hepatic
Rheumatoid arthritis Very long elimination half-life
Blood count and liver function
monitoring required
Monitoring required Nausea
Narrow therapeutic window
Metabolized by hepatic
CYP450 enzymes leading to
interactions
Long elimination half-life of
10–27 h
Monitoring required
CYP450 enzymes, leading to
interactions
Very long elimination half-life
(around 2 weeks)
Monitoring required
(42–128 days) due to
accumulation in tissues
Monitoring required
GI disturbances
Rash and urticaria
Cough
Bone marrow suppression (blood
disorders)
Fever
Vomiting
Diarrhoea
Bone marrow suppression (blood
disorders)
Liver toxicity
Anorexia
GI disturbance
Gum hypertrophy
Nephrotoxicity
Hypertension
Tremor
Liver toxicity
Bone marrow suppression (blood
disorders)
Abdominal pain
Diarrhoea
Nausea
Vomiting
Liver toxicity
Hypersensitivity skin reactions (e.g.
Stevens–Johnson syndrome)
GI disturbance (diarrhoea particularly
with auranofin)
Mouth ulcers
Sore throat
Rash
Blood disorders
Nephrotoxicity
Liver toxicity
Therapeutic class Drugs Mechanism of action Common clinical uses Comments Common adverse drug reactions
236 Chapter 9 Rheumatoid arthritis
Cytokine blockers—
biological agents
1) Anti TNF- agents
Antimalarials:
Chloroquine
Hydroxychloroquine
Penicillamine Mechanism unclear. May
Etanercept Acts as decoy receptor to
Infliximab Chimeric monoclonal
Adalimumab
Golimumab
Interfere with antigen
processing by
macrophages to reduce
T-cell activation, and
downregulate immune
response
May also inhibit
eicosanoid and cytokine
production in
macrophages, and
neutrophil function
involve:
1) reduction in T-cell
proliferation
2) inhibition of collagen
crosslinking
3) reduced formation of
immune complexes of
rheumatoid factor
bind TNF- and reduce
immune response
antibody against TNF-
Humanized monoclonal
antibody directed against
TNF-
Rheumatoid arthritis
Lupus erythematosus
Malaria
Rheumatoid arthritis
Wilson’s disease
Lead/mercury poisoning
Moderate to severe
rheumatoid arthritis
Psoriatic arthritis
Ankylosing spondylitis
Plaque psoriasis
Crohn’s disease
Ulcerative colitis
Long elimination half-life (~50
days) due to accumulation in
tissues
Monitoring required
Used in patients with
extra-articular features, e.g.
vasculitis
Requires monitoring
Used second line under
specialist supervision
Optimum benefit seen in
rheumatoid arthritis when
combined with methotrexate
GI disturbance
Headaches
Skin reactions
ECG changes
Retinopathy
GI disturbance
Rash
Mouth ulcers
Fever
Anorexia
Taste loss
Susceptibility to infection, e.g. latent
tuberculosis
GI disturbance
Worsening heart failure
Injection site reactions
Hypersensitivity (allergic) reactions
Hyperlipidaemia
Hypertension
Certolizumab pegol
Anti TNF- antibody
2) Other cytokine
blockers
Abatacept Blocks T-cell activation by
antigen-presenting cell to
reduce immune response
Tofacitinib Blocks Jak1 and Jak3 to
reduce the effects of
cytokines
Moderate–severe
rheumatoid arthritis
9.6 Choice of treatment for rheumatoid arthritis 237
Infection
GI disturbances
Headache
Dizziness
Cold symptoms
Blood disorders (especially neutropenia)
Hypersensitivity reactions
Injection site reaction
Liver toxicity
Rituximab Monoclonal antibody
Anakinra Recombinant version of
Tocilizumab Monoclonal antibody
directed against a surface
protein on B-cells that
causes cells to lyse
IL-1 receptor antagonist
Blocks pro-inflammatory
effect of IL-1
directed against IL-6
receptors
Reduces pro-inflammatory
effect of IL-6
WORKBOOK 6
Rheumatoid arthritis
Pamela and Gwen: battling with joint disease. Rheumatoid
Pamela: a simplified case history
Whilestrugglingoutofbedat7.30a.m.,Pamelamakesamentalnotetonallytakeher
husband’s advice and consult her GP about the pain and general tiredness she has been
experiencing. She has tried to cope for 4 months, but the condition has worsened, and she is
ready to admit to herself that her symptoms cannot be entirely attributed to the demands of
being a wife and mum to three children. She wonders if the symptoms have anything to do with
her recent road traffic accident, which resulted in three broken ribs and sepsis. She gets an
appointment and heads to the surgery after dropping the children off at school.
After examining her and asking some questions about her symptoms, her GP refers Pamela to a
rheumatologist.
A table of clinical clerking abbreviations is given on page xviii.
CLINICAL CLERKING FOR PAMELA JONES AT RHEUMATOLOGY
CLINIC
Age: 41 years
PC: Morning stiffness lasting for hours accompanied by fatigue, anorexia, muscle and joint pain
The symptoms of rheumatoid arthritis are as follows:
• Morningstiffness(thisisakeyfeature,distinguishingrheumatoidarthritisfromosteoarthritis)
• Jointsarered,swollen,tender,warm,andstiff,leadingtorestrictedmovement
• Jointscommonlyaffectedarecervicalspine(neck),hands,andfeet;wheremultiplejointsare
affected, toes and fingers often become deformed
• Largerjoints,suchaselbows,shoulders,andknees,canalsobeaffected
• Affectedjointshaveasymmetricaldistribution.
HPC: Progressing symptoms of stiffness, pain, and general malaise. Inflammation and swelling around
both knee joints and finger joints.
When taking the patient’s medical history, the doctor will enquire about the duration and pattern of
joint symptoms, and whether there are any other symptoms. The doctor will also try to establish
the impact on daily activities.
WORKBOOK 6 Rheumatoid arthritis 239
Presentation of rheumatoid arthritis
There are three main presentations:
1) mild intermittent symptoms which resolve and then reappear over weeks
2) sudden onset of symptoms followed by a prolonged remission
3) progressive uninterrupted symptoms which result in disabling joint deformities.
Early symptoms are usually non-specific, including fatigue, malaise, diffuse musculoskeletal pain, and
stiffness. The most obvious symptoms are pain and loss of function of joints.
DH: Nil significant
Pamela does not take any regular medication.
PMH: Sepsis (blood infection) following road traffic accident 5 months ago
The doctor must use the diagnostic features of rheumatoid arthritis to exclude the possibility that
Pamela’s symptoms have resulted from the accident.
FH: Pamela’s mother and grandmother both suffered from rheumatoid arthritis
The exact cause of rheumatoid arthritis is unclear, but hormonal, genetic, and environmental
factors all have a role. Her family history increases the likelihood of Pamela suffering from the
condition. Stressful situations and infection (both of which Pamela has encountered recently) are
possible triggers.
O/E: Bilateral symmetrical swelling, warmth, tenderness and redness of metacarpophalangeal joints of
hands. Subcutaneous nodule seen when forearm is extended.
During a physical examination, the joints are examined to observe:
• rangeofmotion
• redness,warmth,andswelling(canbeduetosynovitis,inammationofthejointlining,oran
effusion, a build-up of fluid inside the joint)
• noduleformation
• symmetryofaffectedjoints
Muscles are also examined for signs of weakness, and the skin for presence of nodules (subcutaneous
lumps), another diagnostic feature
Investigations:
Erythrocyte sedimentation rate elevated (normal <10 mm/hour)
C-reactive protein very elevated (normal <5 mg/l)
Haemoglobin decreased (normal: male 13.5–17 g/dl; female
11.5–14.8 g/dl)
Serum iron concentration decreased (normal: male 55–160 g/dl; female
40–155 g/dl)
Total iron-binding capacity decreased (range 255–450 g/dl)
Alkaline phosphatase slightly elevated (normal 20–130 IU/l)
Serum albumin decreased (normal 35–50 g/l)
Rheumatoid factor positive
Anti-cyclic citrullinated peptide antibodies positive
240 Chapter 9 Rheumatoid arthritis
Laboratory tests help to confirm the diagnosis of rheumatoid arthritis and to distinguish it from
other similar conditions.
In diagnosis, markers of inflammation, such as erythrocyte sedimentation rate and C-reactive
protein, are useful for distinguishing inflammatory arthritis (e.g. rheumatoid arthritis) from
non-inflammatory osteoarthritis. Levels of both are usually, but not invariably, elevated in
rheumatoid arthritis. These tests are also useful for monitoring response to treatment.
Pamela’s haemoglobin level is decreased, indicating anaemia. Inflammatory diseases such as
rheumatoid arthritis are commonly associated with a form of non-iron-deficiency anaemia, termed
anaemia of chronic disease. Her serum iron concentration and total iron-binding capacity are also
decreased, indicative of this condition.
Liver function test results (alkaline phosphatase and albumin) are often deranged in rheumatoid
arthritis.
Rheumatoid factor is an autoantibody, found in 70–80% of patients with arthritis. It is, though, also
present in a number of other conditions (e.g. infections and chronic lung and liver disease) and in
around 5% of healthy individuals.
Anti-cyclic citrullinated peptide antibodies are more specific for rheumatoid arthritis than
rheumatoid factor. This test is useful for early detection of the disease.
Other investigations:
1) Synovial fluid analysis: positive
Small samples of synovial fluid (the fluid around the joint) can be withdrawn and analysed. In
rheumatoid arthritis its composition is altered, with increased levels of immune cells (e.g. white
blood cells).
2) X-rays: No visible changes
X-rays can show evidence of erosion of cartilage and bone as rheumatoid arthritis progresses, and
can therefore be useful for monitoring the condition over time. X-rays are not usually helpful for
detecting rheumatoid arthritis in its early stages.
Pamela had no changes visible on X-ray, as is usually the case in early disease.
About 15–30% of patients have changes detectable by X-ray in the first year, whereas after two years
the figure is more than 90%. X-rays can also help to measure bone mineral density, often decreased
in the later stages of rheumatoid arthritis.
3) Magnetic resonance imaging: not performed on Pamela
Magnetic resonance imaging (MRI) scans are more sensitive than X-rays for detecting the bone
damage caused by rheumatoid arthritis, and may therefore be better for detecting early
deterioration. MRI scans are also useful for assessing changes in the synovium (the joint lining) and
for assessing compression of the cervical spinal cord. They are, though, very costly and are not
widely used to diagnose or follow the course of rheumatoid arthritis.
An MRI scan was not warranted in Pamela’s case.
Diagnosis: Early mildly active rheumatoid arthritis
Diagnosis of rheumatoid arthritis is made following review of symptoms, results of laboratory tests,
and radiological findings. Rheumatologists are aided in diagnosis by criteria developed collaboratively
in 2010 by the American College of Rheumatology (ADR) and the European League Against
Rheumatism (EULAR). These criteria focus on early changes in the disease, so as to avoid delay in
diagnosis and the initiation of therapy.
WORKBOOK 6 Rheumatoid arthritis 241
Family history is also taken into account. In Pamela’s case the combination of factors makes
diagnosis straightforward.
Plan:
Diclofenac
Sulfasalazine
Diclofenac is a non-selective NSAID with lasting analgesic and anti-inflammatory effects, making it
particularly useful for the treatment of continuous or regular pain associated with inflammation.
Sulfasalazine is a disease-modifying anti-rheumatic drug (DMARD) which suppresses the
inflammatory activity in rheumatoid arthritis.
PART 1
1a) What is rheumatoid arthritis?
1b) Describe the pathogenesis of rheumatoid arthritis.
2) What are the initial approaches to the treatment of rheumatoid arthritis?
After 2 months Pamela goes to her pharmacy and requests Gaviscon® for indigestion. The
pharmacist,whorecognizesher,checksherhistoryonthecomputerandseesthatPamelahad
lansoprazole3yearspreviously.
On enquiry she ascertains that Pamela had suffered from gastritis when taking ibuprofen. Pam
says she had not mentioned this to the rheumatologist when he had asked her about adverse
reactions to drugs, because she had bought the ibuprofen over the counter and so had not
considered it as a drug in the same way as prescribed medication.
The pharmacist asks Pamela to describe her exact symptoms, after which she advises Pamela
to see her doctor urgently, as she suspects Pamela might have a recurrence of gastritis.
3) Explain why NSAIDs have gastrointestinal effects.
4a) What is the role of corticosteroids in rheumatoid arthritis?
4b) Describe the mechanism of action of corticosteroids.
When Pamela sees her GP the following day, he prescribes celecoxib in place of diclofenac.
5) Explain the difference between diclofenac and celecoxib.
6) List two patient groups who should not be prescribed celecoxib, and explain why not.
7a) What are the advantages of sulfasalazine over other DMARDs?
7b) What is the mechanism of action of sulfasalazine?