Osteoporosis: causes

Long-term use of proton pump inhibitors is associated with reduced bone mineral density

Low body mass, rather than obesity is associated with an increased risk of developing
osteoporosis
Advancing age and female sex are significant risk factors for osteoporosis. Prevalence of
osteoporosis increases from 2% at 50 years to more than 25% at 80 years in women.

There are many other risk factors and secondary causes of osteoporosis. We'll start by looking
at the most 'important' ones - these are risk factors that are used by major risk assessment
tools such as FRAX:

 history of glucocorticoid use

 rheumatoid arthritis
 alcohol excess
 history of parental hip fracture
 low body mass index
 current smoking

Other risk factors

 sedentary lifestyle
 premature menopause
 Caucasians and Asians
 endocrine disorders: hyperthyroidism, hypogonadism (e.g. Turner's, testosterone
deficiency), growth hormone deficiency, hyperparathyroidism, diabetes mellitus
 multiple myeloma, lymphoma
 gastrointestinal disorders: inflammatory bowel disease, malabsorption (e.g. Coeliac's),
gastrectomy, liver disease
 chronic kidney disease
 osteogenesis imperfecta, homocystinuria

Medications that may worsen osteoporosis (other than glucocorticoids):

 long term heparin therapy

 proton pump inhibitors
 glitazones
 aromatase inhibitors e.g. anastrozole.

1
Investigations for secondary causes
If a patient is diagnosed with osteoporosis or has a fragility fracture further investigations may
be warranted. NOGG recommend testing for the following reasons:

 exclude diseases that mimic osteoporosis (e.g. osteomalacia, myeloma);

 identify the cause of osteoporosis and contributory factors;
 assess the risk of subsequent fractures;
 select the most appropriate form of treatment

The following investigations are recommended by NOGG:

 History and physical examination

 Blood cell count, sedimentation rate or C-reactive protein, serum calcium,albumin,
creatinine, phosphate, alkaline phosphatase and liver transaminases
 Thyroid function tests
 Bone densitometry ( DXA)

Other procedures, if indicated

 Lateral radiographs of lumbar and thoracic spine/DXA-based vertebral imaging

 Protein immunoelectrophoresis and urinary Bence-Jones proteins
 25OHD
 PTH
 Serum testosterone, SHBG, FSH, LH (in men),
 Serum prolactin
 24 hour urinary cortisol/dexamethasone suppression test
 Endomysial and/or tissue transglutaminase antibodies (coeliac disease)
 Isotope bone scan
 Markers of bone turnover, when available
 Urinary calcium excretion

So from the first list we should order the following bloods as a minimum for all patients:

 full blood count

 urea and electrolytes
 liver function tests
 bone profile
 CRP
 thyroid function tests.

2
Osteoporosis: glucocorticoid-induced
Bone protection for patients who are going to take long-term steroids should start immediately

Bone protection for patients taking corticosteroids

 < 65 years: DEXA scan first

 >= 65 years: start alendronate

We know that one of the most important risk factors for osteoporosis is the use of
corticosteroids. As these drugs are so widely used in clinical practice it is important we manage
this risk appropriately. 
The most widely followed guidelines are based around the 2002 Royal College of Physicians
(RCP) 'Glucocorticoid-induced osteoporosis: A concise guide to prevention and treatment'.

The risk of osteoporosis is thought to rise significantly once a patient is taking the equivalent of
prednisolone 7.5mg a day for 3 or more months. It is important to note that we should manage
patients in an anticipatory, i.e. if it likely that the patient will have to take steroids for at least 3
months then we should start bone protection straight away, rather than waiting until 3 months
has elapsed. A good example is a patient with newly diagnosed polymyalgia rheumatica. As it is
very likely they will be on a significant dose of prednisolone for greater than 3 months bone
protection should be commenced immediately.

Management of patients at risk of corticosteroid-induced osteoporosis

The RCP guidelines essentially divide patients into two groups.

1. Patients over the age of 65 years or those who've previously had a fragility fracture should be
offered bone protection. 
2. Patients under the age of 65 years should be offered a bone density scan, with further
management dependent:

3
 T score Management

Greater than 0 Reassure

Between 0 and -1.5 Repeat bone density scan in 1-3 years

Less than -1.5 Offer bone protection

The first-line treatment is alendronate. Patients should also be calcium and vitamin D replete.

Osteoporosis: assessing risk

Radiographs may show osteopenia but it is not possible to determine the severity of
osteopenia/osteoporosis accurately using this method alone. Calcium and phosphate levels are
normal in osteoporosis.

There is no such thing as a Birmingham Hip Score tool.

We worry about osteoporosis because of the increased risk of fragility fractures. So how do we
assess which patients are at risk and need further investigation?

NICE produced guidelines in 2012: Osteoporosis: assessing the risk of fragility fracture. The
following is based on those guidelines.

They advise that all women aged >= 65 years and all men aged >= 75 years should be assessed.
Younger patients should be assessed in the presence of risk factors, such as:

 previous fragility fracture

 current use or frequent recent use of oral or systemic glucocorticoid
 history of falls
 family history of hip fracture
 other causes of secondary osteoporosis
 low body mass index (BMI) (less than 18.5 kg/m²)
 smoking
 alcohol intake of more than 14 units per week for women and more than 21 units per
week for men.

4
Methods of risk assessment

NICE recommend using a clinical prediction tool such as FRAX or QFracture to assess a patients
10 year risk of developing a fracture. This is analogous to the cardiovascular risk tools such as
QRISK.

FRAX

 estimates the 10-year risk of fragility fracture

 valid for patients aged 40-90 years
 based on international data so use not limited to UK patients
 assesses the following factors: age, sex, weight, height, previous fracture, parental
fracture, current smoking, glucocorticoids, rheumatoid arthritis, secondary
osteoporosis, alcohol intake
 bone mineral density (BMD) is optional, but clearly improves the accuracy of the results.
NICE recommend arranging a DEXA scan if FRAX (without BMD) shows an intermediate
result

QFracture

 estimates the 10-year risk of fragility fracture

 developed in 2009 based on UK primary care dataset
 can be used for patients aged 30-99 years (this is stated on the QFracture website, but
other sources give a figure of 30-85 years)
 includes a larger group of risk factors e.g. cardiovascular disease, history of falls, chronic
liver disease, rheumatoid arthritis, type 2 diabetes and tricyclic antidepressants

There are some situations where NICE recommend arranging BMD assessment (i.e. a DEXA
scan) rather than using one of the clinical prediction tools:

 before starting treatments that may have a rapid adverse effect on bone density (for
example, sex hormone deprivation for treatment of breast or prostate cancer).
 in people aged under 40 years who have a major risk factor, such as history of multiple
fragility fracture, major osteoporotic fracture, or current or recent use of high-dose oral
or high-dose systemic glucocorticoids (more than 7.5 mg prednisolone or equivalent per
day for 3 months or longer).

Interpreting the results of FRAX

Once we've decided that we need to do a risk assessment using FRAX and have entered all the
data we are left with results to interpret.

5
If the FRAX assessment was done without a bone mineral density (BMD) measurement the
results (10-year risk of a fragility fracture) will be given and categorised automatically into one
of the following:

 low risk: reassure and give lifestyle advice

 intermediate risk: offer BMD test
 high risk: offer bone protection treatment

Therefore, with intermediate risk results FRAX will recommend that you arrange a BMD test to
enable you to more accurately determine whether the patient needs treatment

If the FRAX assessment was done with a bone mineral density (BMD) measurement the results
(10-year risk of a fragility fracture) will be given and categorised automatically into one of the
following:

 reassure
 consider treatment
 strongly recommend treatment

If you use QFracture instead patients are not automatically categorised into low, intermediate
or high risk. Instead the 'raw data' relating to the 10-year risk of any sustaining an osteoporotic
fracture. This data then needs to be interpreted alongside either local or national guidelines,
taking into account certain factors such as the patient's age.

When should we reassess a patient's risk?

NICE recommend that we recalculate a patient's risk (i.e. repeat the FRAX/QFracture):

 if the original calculated risk was in the region of the intervention threshold for a
proposed treatment and only after a minimum of 2 years, or
 when there has been a change in the person's risk factors

Osteoporosis: DEXA scan

Basics

 T score: based on bone mass of young reference population

 T score of -1.0 means bone mass of one standard deviation below that of young
reference population
 Z score is adjusted for age, gender and ethnic factors

6
T score

 > -1.0 = normal

 -1.0 to -2.5 = osteopaenia
 < -2.5 = osteoporosis

Osteoporosis: Assessing patients following a fragility fracture

Start alendronate in patients >= 75 years following a fragility fracture, without waiting for a
DEXA scan

 The management of patients following a fragility fracture depends on age.

Patients >= 75 years of age

Patients who've had a fragility fracture and are >= 75 years of age are presumed to have
underlying osteoporosis and should be started on first-line therapy (an oral
bisphosphonate), without the need for a DEXA scan.

It should be noted that the 2014 NOGG guidelines have a different threshold, suggesting
treatment is started in all women over the age of 50 years who've had a fragility fracture
- 'although BMD measurement may sometimes be appropriate, particularly in younger
postmenopausal women.'

Patients < 75 years of age

If a patient is under the age of 75 years a DEXA scan should be arranged. These results
can then be entered into a FRAX assessment (along with the fact that they've had a
fracture) to determine the patients ongoing fracture risk.

7
 For example, a 79-year-old woman falls over on to an outstretched hand and sustains a
Colles' fracture (fracture of the distal radius). Given her age she is presumed to have
osteoporosis and therefore started on oral alendronate 70mg once weekly. No DEXA
scan is arranged.

Osteoporosis: management
The 2008 NICE guidelines suggest switching to risedronate or etidronate in patients unable to
tolerate alendronate
NICE guidelines were updated in 2008 on the secondary prevention of osteoporotic fractures in
postmenopausal women.
Alendronate is the first-line bisphosphonate for patients at risk of fragility fracture; risedronate
should be prescribed as second-line if alendronate is not tolerated. Both can be prescribed as
either weekly, or smaller daily, doses. If the patient cannot tolerate either alendronate or
risedronate, they should be referred to a specialist for consideration of other treatments such
as strontium ranelate or raloxifene. Hormone replacement therapy is generally only used for
the prevention of fragility fractures in women who have experienced menopause prior to the
age of 45 (and only continued until age 50).

Key points include

 treatment is indicated following osteoporotic fragility fractures in postmenopausal

women who are confirmed to have osteoporosis (a T-score of - 2.5 SD or below). In
women aged 75 years or older, a DEXA scan may not be required 'if the responsible
clinician considers it to be clinically inappropriate or unfeasible'
 vitamin D and calcium supplementation should be offered to all women unless the
clinician is confident they have adequate calcium intake and are vitamin D replete
 alendronate is first-line
 around 25% of patients cannot tolerate alendronate, usually due to upper
gastrointestinal problems. These patients should be offered risedronate or etidronate
(see treatment criteria below)
 strontium ranelate and raloxifene are recommended if patients cannot tolerate
bisphosphonates (see treatment criteria below)

Treatment criteria for patients not taking alendronate

Unfortunately, a number of complicated treatment cut-off tables have been produced in the
latest guidelines for patients who do not tolerate alendronate
These take into account a patients age, their T-score and the number of risk factors they have
from the following list:

 parental history of hip fracture

8
  alcohol intake of 4 or more units per day
 rheumatoid arthritis

It is very unlikely that examiners would expect you to have memorised these risk tables so
we've not included them in the revision notes but they may be found by following the NICE link.
The most important thing to remember is:

 the T-score criteria for risedronate or etidronate are less than the others implying that
these are the second line drugs
 if alendronate ( Fosamax ) , risedronate or etidronate cannot be taken then strontium
ranelate or raloxifene ( Evista ) may be given based on quite strict T-scores (e.g. a 60-
year-old woman would need a T-score < -3.5)
 the strictest criteria are for denosumab

Supplementary notes on treatment

Bisphosphonates

 alendronate, risedronate and etidronate are all licensed for the prevention and
treatment of post-menopausal and glucocorticoid-induced osteoporosis
 all three have been shown to reduce the risk of both vertebral and non-vertebral
fractures although alendronate, risedronate may be superior to etidronate in preventing
hip fractures
 ibandronate is a once-monthly oral bisphosphonate

Vitamin D and calcium

 poor evidence base to suggest reduced fracture rates in the general population at risk of
osteoporotic fractures - may reduce rates in frail, housebound patients

Raloxifene - selective oestrogen receptor modulator (SERM)

 has been shown to prevent bone loss and to reduce the risk of vertebral fractures, but
has not yet been shown to reduce the risk of non-vertebral fractures
 has been shown to increase bone density in the spine and proximal femur
 may worsen menopausal symptoms
 increased risk of thromboembolic events
 may decrease risk of breast cancer

9
Strontium ranelate  ( protelos )

 'dual action bone agent' - increases deposition of new bone by osteoblasts (promotes
differentiation of pre-osteoblast to osteoblast) and reduces the resorption of bone by
inhibiting osteoclasts
 concerns regarding the safety profile of strontium have been raised recently. It should
only be prescribed by a specialist in secondary care
 due to these concerns the European Medicines Agency in 2014 said it should only be
used by people for whom there are no other treatments for osteoporosis
 increased risk of cardiovascular events: any history of cardiovascular disease or
significant risk of cardiovascular disease is a contraindication
 increased risk of thromboembolic events: a Drug Safety Update in 2012 recommended it
is not used in patients with a history of venous thromboembolism
 may cause serious skin reactions such as Stevens Johnson syndrome

Denosumab

 human monoclonal antibody that inhibits RANK ligand, which in turn inhibits the
maturation of osteoclasts
 given as a single subcutaneous injection every 6 months
 initial trial data suggests that it is effective and well tolerated

Teriparatide

 recombinant form of parathyroid hormone

 very effective at increasing bone mineral density but role in the management of
osteoporosis yet to be clearly defined

Hormone replacement therapy

 has been shown to reduce the incidence of vertebral fracture and non-vertebral
fractures
 due to concerns about increased rates of cardiovascular disease and breast cancer it is
no longer recommended for primary or secondary prevention of osteoporosis unless the
woman is suffering from vasomotor symptoms

10
Hip protectors

 evidence suggests significantly reduce hip fractures in nursing home patients

 compliance is a problem

Falls risk assessment

 no evidence to suggest reduced fracture rates

 however, do reduce rate of falls and should be considered in management of high risk
patients.

MRI showing osteoporotic fractures of the 8th and 10th thoracic vertebrae.

Osteoporosis: therapeutic management

The 2008 NICE guidelines probably provide the most comprehensive guidance on the use of
specific therapies for osteoporosis.

The recommend first-line treatment is oral alendronate. This is usually taken once weekly at a
dose of 70mg. It is tolerated in around 75% of patients.

If oral alendronate is not tolerated NICE recommend the use of risk tables to see whether it is
'worth' trying another treatment. The tables display a minimum T score based on a patients age
and number of clinical risk factors.

11
These are not reproduced here but may be found in the links section.

Clearly a degree of clinical judgement may be required when determining the best course of
action, particularly as the guidelines were released in 2008.

Assuming that it is thought appropriate to try another treatment alternative oral

bisphosphonates (either risedronate or etidronate) are recommended as the second-line
treatment. NICE recommend that risedronate and etidronate are suitable for both the primary
and secondary prevention of fragility fractures.

What does NICE recommend if bisphosphonates are not tolerated?

Again NICE recommend that we review some risk tables based on minimum T scores to see if
further treatment is indicated. If it is then strontium ranelate or raloxifene are recommended.

Strontium ranelate 

 'dual action bone agent' - increases deposition of new bone by osteoblasts (promotes
differentiation of pre-osteoblast to osteoblast) and reduces the resorption of bone by
inhibiting osteoclasts
 concerns regarding the safety profile of strontium have been raised recently. It should
only be prescribed by a specialist in secondary care
 due to these concerns the European Medicines Agency in 2014 said it should only be
used by people for whom there are no other treatments for osteoporosis
 increased risk of cardiovascular events: any history of cardiovascular disease or
significant risk of cardiovascular disease is a contraindication
 increased risk of thromboembolic events: a Drug Safety Update in 2012 recommended it
is not used in patients with a history of venous thromboembolism
 may cause serious skin reactions such as Stevens Johnson syndrome

Raloxifene - selective oestrogen receptor modulator (SERM)

 has been shown to prevent bone loss and to reduce the risk of vertebral fractures, but
has not yet been shown to reduce the risk of non-vertebral fractures
 has been shown to increase bone density in the spine and proximal femur
 may worsen menopausal symptoms
 increased risk of thromboembolic events
 may decrease risk of breast cancer

Osteoporosis: calcium and vitamin D supplementation

Calcium supplementation has been linked to an increased risk of myocardial infarction

12
In the 2008 NICE guidelines on the secondary prevention of osteoporotic fractures in
postmenopausal women it is advised that 'This guidance assumes that women who receive
treatment have an adequate calcium intake and are vitamin D replete. Unless clinicians are
confident that women who receive treatment meet these criteria, calcium and/or vitamin D
supplementation should be considered.'

So, we should just prescribe everyone a combined calcium and vitamin D supplement?

The problem is that there seems to be a potential downside to this approach. For many years
there has been concern about the potential for calcium supplements to increase the risk of
ischaemic heart disease. A large meta-analysis in the BMJ in 2010 (BMJ 2010; 341; c3691) was
the first warning shot. This study was criticised at time for looking at some patients who
weren't co-prescribed vitamin D. However, a subsequent analysis of this study and two later
studies seems to confirm the association.
One of these later studies was published in Heart in 2012 (Heart 2012;98:920-925). It looked at
over 23,000 and found patients who had been taking calcium supplements had a significantly
increased risk of myocardial infarction (hazard ratio = 2.39; 95% CI 1.12 to 5.12). This same risk
was not seen for patients with high calcium intake via normal dietary means.

None of the major guideline bodies have offered advice about what we should do in this
situation. For the time being it seems sensible to encourage people to aim for a dietary calcium
intake of around 1,000mg / day where possible and prescribe a standalone vitamin D
supplement (usually 10mcg/day), which have become increasingly in recent years.

Strontium ranelate
Any form of cardiovascular disease is a contraindication to strontium ranelate

There are now significant safety concerns regarding the cardiovascular side-effects of strontium
ranelate, a drug used in the management of osteoporosis. It should not be used in patients with
a history of cardiovascular disease.
Strontium ranelate is used in the management of osteoporosis. It is a 'dual action bone agent' -
increasing deposition of new bone by osteoblasts (promotes differentiation of pre-osteoblast to
osteoblast) and reduces the resorption of bone by inhibiting osteoclasts.

In the past guidelines have recommended strontium ranelate when oral bisphosphonates were
either not tolerated or contraindicated.

Adverse effects

Strontium ranelate is associated with severe skin reactions such as drug rash with eosinophilia
and systemic symptoms (DRESS) syndrome.

13
There is also an increased risk of venous thromboembolism a Drug Safety Update in 2012
recommended it is not used in patients with a history of venous thromboembolism

What does the 2013 Drug Safety Update add?

A study raised significant concerns about the increased risk of cardiovascular disease in patients
taking strontium ranelate, with a relative risk of myocardial infarction of 1.6.

The MHRA advised that strontium ranelate should therefore only be prescribed by a specialist
to patients with severe osteoporosis:

 in postmenopausal women at high risk of fracture

 in men at increased risk of fracture

Any form of cardiovascular disease or uncontrolled hypertension is a contraindication to

strontium ranelate.

UPDATE - 2014

Following the MHRA warning in 2013 and further evidence the European Medicines Agency in
2014 said it should only be used by people for whom there are no other treatments for
osteoporosis.

Denosumab
Denosumab is generally well tolerated but may cause atypical femoral fractures

Denosumab is a relatively new treatment for osteoporosis. It is a human monoclonal antibody

that inhibits osteoclast formation, function and survival. Remember that osteoblasts build
bone, osteoclasts eat bone. It is given as a subcutaneous injection, at a dose of 60mg, every 6
months.
A larger dose of denosumab (120mg) may also be given every 4 weeks for the prevention of
skeletal-related events (i.e. pathological fractures) in adults with bone metastases from solid
tumours. For example, you may have noticed some of your breast cancer patients have been
prescribed denosumab.

Where does it fit in the management of osteoporosis?

Oral bisphosphonates are still given first-line, with oral alendronate being the first-line
treatment. If alendronate is not tolerated then NICE recommend using an alternative
bisphosphonate - either risedronate or etidronate. Following this the advice becomes more
complicated with the next-line medications only being started if certain T score and other risk
factor criteria being met. Raloxifene and strontium ranelate were recommended as next-line

14
drugs in the NICE criteria but following recent safety concerns regarding strontium ranelate it is
likely there will be an increasing role for denosumab.

NICE published a technology appraisal looking at the role of denosumab in 2010. A link is
provided.

What are the known side-effects of denosumab?

Denosumab is generally well tolerated. Dyspnoea and diarrhoea are generally considered the
two most common side effects, occuring in around 1 in 10 patients. Other less common side
effects include hypocalcaemia and upper respiratory tract infections.

What does the Drug Safety Update add?

Cases of atypical femoral fractures have been noted in patients taking denosumab. Doctors are
advised to look out for patients complaining of unusual thigh, hip or groin pain.

Osteoporosis: monitoring treatment

Two of the main questions that patients ask after starting bone protection treatment are:

 How do I know if the treatment is working? Should we repeat the DEXA scan?
 How long do I need to stay on treatment?

Unfortunately there is little clear guidance from the major guidelines relating to these issues.

What is the consensus view?

The general consensus is that patients do not require assessment of bone mineral density once
bone protection has been started. This is partly because there is limited evidence of any link
between improvement in bone mineral density and reduction in fracture risk.

With respect to length of treatment, the NOGG state the following in their patient-information
leaflet (more detail seems to be given here than the guidelines aimed at healthcare
professionals!)

A treatment review is recommended after 5 years of treatment for alendronate, risedronate or

ibandronate and after 3 years for zoledronic acid. The review is likely to involve a recalculation
of your fracture risk and a DXA scan.

Hormone replacement therapy: indications

Hormone replacement therapy (HRT) involves the use of a small dose of oestrogen, combined
with a progestogen (in women with a uterus), to help alleviate menopausal symptoms. 
15
The indications for HRT have changed significantly over the past ten years as the long-term risks
became apparent, primarily as a result of the Women's Health Initiative (WHI) study. 

Indications

 vasomotor symptoms such as flushing, insomnia and headaches

 premature menopause: should be continued until the age of 50 years. Most important
reason is preventing the development of osteoporosis

The main indication is the control of vasomotor symptoms. The other indications such as
reversal of vaginal atrophy should be treated with other agents as first-line therapies

Other benefits include a reduced incidence of colorectal cancer

NICE recommends that women who go through the menopause prior to the age of 45 should
consider taking hormone replacement therapy, to reduce the risk of developing osteoporosis
and also to manage menopausal symptoms. It should be reviewed at age 50. The patient should
also be offered lifestyle advice for bone health i.e. take weight bearing exercise, stop smoking,
not consume excess alcohol, and ensure adequate intake of calcium and vitamin D.

Gout: management

Na+ 136 mmol/l

K+ 4.6 mmol/l

Urea 12 mmol/l

Creatinine 140 µmol/l

Uric acid 300 µmol/l (200-420µmol/l)

What is the best treatment?

This man has an acute episode of gout. The uric acid levels can be normal as they are
sequestered into the joint space. 

Allopurinol reduces uric acid production and is useful for gout prophylaxis but should not be
started during an acute flare. NSAIDs are relatively contraindicated by the ischaemic heart
disease, renal dysfunction and hiatus hernia. Aspirin is generally not used for gout.
Prednisolone is relatively contraindicated by the high blood pressure, osteoporosis and hiatus

16
hernia. This leaves colchicine as the best treatment choice. A steroid joint injection would be a
reasonable alternative but may be detrimental to local osteoporosis

Gout: start allopurinol if >= 2 attacks in 12 month period

Diclofenac and indomethacin are contraindicated for pt with duodenal ulcer. Colchicine is a
suitable alternative. Allopurinol should not be given in the acute phase, but is good for
preventing recurrent attacks.

NSAIDs should be avoided in elderly patients taking warfarin due to the risk of a life-threatening
gastrointestinal haemorrhage. Oral steroids are an option but would upset his diabetic control.

Whilst anticoagulation is not a contraindication to joint injection it would make this option less
attractive.

Gout can be a precursor to conditions such as ischaemic heart disease and hypertension, which
should be investigated for. 
Weight loss and alcohol avoidance should be encouraged in patients with gout.

Gout is a form of microcrystal synovitis caused by the deposition of monosodium urate

monohydrate in the synovium. It is caused by chronic hyperuricaemia (uric acid > 450 µmol/l)

Acute management

 NSAIDs
 intra-articular steroid injection
 colchicine* has a slower onset of action. The main side-effect is diarrhea . Colchicine is
useful in patients with renal impairment who develop gout as NSAIDs are relatively
contraindicated. The BNF advises to reduce the dose by up to 50% if creatinine
clearance is less than 50 ml/min and to avoid if creatinine clearance is less than 10
ml/min.
Co-codamol 30/500 may be used as an adjunct but would not provide relief as
monotherapy.
Prednisolone is an option but would adversely affect his diabetic control.
 oral steroids may be considered if NSAIDs and colchicine are contraindicated. A dose of
prednisolone 15mg/day is usually used
 if the patient is already taking allopurinol it should be continued

Allopurinol prophylaxis - see indications below

 allopurinol should not be started until 2 weeks after an acute attack has settled as it may
precipitate a further attack if started too early

17
  initial dose of 100 mg od, with the dose titrated every few weeks to aim for a serum uric
acid of < 300 µmol/l
 NSAID or colchicine cover should be used when starting allopurinol

Indications for allopurinol**

 recurrent attacks - the British Society for Rheumatology recommend 'In uncomplicated
gout uric acid lowering drug therapy should be started if a second attack, or further
attacks occur within 1 year'
 tophi
 renal disease
 uric acid renal stones
 prophylaxis if on cytotoxics or diuretics

Lifestyle modifications

 reduce alcohol intake and avoid during an acute attack

 lose weight if obese
 avoid food high in purines e.g. Liver, kidneys, seafood, oily fish (mackerel, sardines) and
yeast products

Other points

 losartan has a specific uricosuric action and may be particularly suitable for the many
patients who have coexistant hypertension
 calcium channel blockers also increase uric acid levels, possibly by a renal vasodilatory
effect
 increased vitamin C intake (either supplements or through normal diet) may also
decrease serum uric acid levels

*inhibits microtubule polymerization by binding to tubulin, interfering with mitosis. Also

inhibits neutrophil motility and activity
**patients with Lesch-Nyhan syndrome often take allopurinol for life

Gout: drug causes

Gout is a form of microcrystal synovitis caused by the deposition of monosodium urate
monohydrate in the synovium. It is caused by chronic hyperuricaemia (uric acid > 0.45 mmol/l)

18
Drug causes

 thiazides, furosemide
 alcohol
 cytotoxic agents
 pyrazinamide
 Aspirin in a dose of 75-150mg is not thought to have a significant effect on plasma urate
levels - please see the British Society for Rheumatology guidelines for more details.
A 45 year old man wearing sandals, hobbles into the consulting room. He reports terrible pain
in the 'ball of his left foot' which is much worse when he walks. It started overnight and he's
never had anything like this before. He's just returned from an enjoyable and relaxing holiday to
the South of France, and can't recall injuring his foot. 

On examination he has a red, inflamed and very tender 1st metatarsal-phalangeal joint of the
left foot. 
Which of the following is the most appropriate management regarding his serum uric acid
level?

This man clearly has acute gout and should be prescribed an appropriate medication to relieve
his pain. According to NICE, NSAIDs are now first line (with appropriate PPI cover), colcicine is
second line and prednisolone third line. 

He has likely overindulged whilst on holiday with a high purine intake (e.g. alcohol, red meat,
seafood, cheese), which has precipitated this episode.

As well as symptomatic management, his uric acid levels should be considered to reduce his risk
of recurrence. Lifestyle advice is important (see below) but NICE advise that the patient is
followed up and serum uric acid levels are checked 4-6 weeks after the acute attack. 

Lifestyle advice for people with gout:

 Aim for an ideal body weight but avoid crash dieting and high protein/low carbohydrate
diets.
 Eat sensibly by restricting the amount of red meat and avoiding a high protein intake.
Avoid excessive consumption of foods rich in purines (such as liver, kidneys, and
seafood).
 Drink alcohol sensibly by avoiding binge drinking and restricting alcohol consumption to
21 units per week for men and 14 units per week for women, with at least two alcohol-
free days a week.
 Avoid dehydration by drinking water (up to 2 litres/day unless there is a medical
contraindication).
 Drink skimmed milk or consume low-fat dairy products (up to 2 servings daily).

19
  Limit consumption of sugary drinks and snacks.
 Take regular exercise but avoid intense muscular exercise and trauma to joints.
 Stop smoking see CKS topic on Smoking cessation.
 Consider taking vitamin C supplements.

Followup (at 4-6 weeks):

 Check the Serum uric acid level.

 Measure the blood pressure and take blood for fasting glucose, renal function, and lipid
profile.
 Identify and manage underlying conditions such as hypertension, diabetes, or renal
impairment, and assess the person's overall cardiovascular risk.
 Provide advice on risk factors such as obesity, diet, excessive alcohol consumption, and
exercise.
 Consider prophylactic medication if a person is having two or more attacks of gout in a
year.
 Consider providing an advance prescription of effective treatment for future attacks of
gout.

Urate lowering treatment (e.g. allopurinol) should be given if the person has two or more
attacks in a year, regardless of their uric acid levels. It should also be considered in those with a
very high uric acid level of 600 micromol/L or more, who have evidence of end organ damage,
or who have other risk factor.

Pseudogout

Pseudogout is a form of microcrystal synovitis caused by the deposition of calcium

pyrophosphate dihydrate in the synovium

20
Risk factors

 hyperparathyroidism
 hypothyroidism
 haemochromatosis
 acromegaly
 low magnesium, low phosphate
 Wilson's disease

Features

 knee, wrist and shoulders most commonly affected

 joint aspiration: weakly-positively birefringent rhomboid shaped crystals
 x-ray: chondrocalcinosis

Management

 aspiration of joint fluid, to exclude septic arthritis

 NSAIDs or intra-articular, intra-muscular or oral steroids as for gout

In a plain X-Ray >> Some loss of joint space

Linear calcification of the articular cartilage

This x-ray describes chondrocalcinosis. Non-specific changes such as loss of joint space are
common in this age group and pseudogout itself may cause osteoarthritic-like changes.

Rheumatoid arthritis: epidemiology

The prevalence of rheumatoid arthritis in the UK population is approximately 1%

Epidemiology

 peak onset = 30-50 years, although occurs in all age groups

 F:M ratio = 3:1
 prevalence = 1%
 some ethnic differences e.g. high in Native Americans
 associated with HLA-DR4 (especially Felty's syndrome)

Rheumatoid arthritis: respiratory manifestations

21
A variety of respiratory problems may be seen in patients with rheumatoid arthritis:

 pulmonary fibrosis
 pleural effusion
 pulmonary nodules
 bronchiolitis obliterans
 complications of drug therapy e.g. methotrexate pneumonitis
 pleurisy
 Caplan's syndrome - massive fibrotic nodules with occupational coal dust exposure
 infection (possibly atypical) secondary to immunosuppression

Rheumatoid arthritis: diagnosis

Anti-cyclic citrullinated peptide antibodies are associated with rheumatoid arthritis

Anti-cyclic citrullinated peptide antibody is highly specific for rheumatoid arthritis.

NICE have stated that clinical diagnosis is more important than criteria such as those defined by
the American College of Rheumatology.

2010 American College of Rheumatology criteria

Target population. Patients who

 1) have at least 1 joint with definite clinical synovitis

 2) with the synovitis not better explained by another disease

Classification criteria for rheumatoid arthritis (add score of categories A-D;

a score of 6/10 is needed definite rheumatoid arthritis)

Key

 RF = rheumatoid factor
 ACPA = anti-cyclic citrullinated peptide antibody

22
Factor Scoring

A. Joint involvement

1 large joint 0

2 - 10 large joints 1

1 - 3 small joints (with or without 2

involvement of large joints)

4 - 10 small joints (with or without 3

involvement of large joints)

10 joints (at least 1 small joint) 5

B. Serology (at least 1 test result is needed for

classification)

Negative RF and negative ACPA 0

Low-positive RF or low-positive ACPA 2

High-positive RF or high-positive ACPA 3

C. Acute-phase reactants (at least 1 test result is

needed for classification)

Normal CRP and normal ESR 0

Abnormal CRP or abnormal ESR 1

D. Duration of symptoms

23
 Factor Scoring

< 6 weeks 0

> 6 weeks 1

Negative bloods do not exclude a diagnosis of rheumatoid and she should be referred to
rheumatology.

Rheumatoid factor
Anti-cyclic citrullinated peptide antibodies are associated with rheumatoid arthritis

Anti-cyclic citrullinated peptide antibody may be detectable up to 10 years before the

development of rheumatoid arthritis. It may therefore play a key role in the future of
rheumatoid arthritis, allowing early detection of patients suitable for aggressive anti-TNF
therapy. It has a sensitivity similar to rheumatoid factor (70-80%, see below) with a much
higher specificity of 90-95%.

NICE recommends that patients with suspected rheumatoid arthritis who are rheumatoid factor
negative should be test for anti-CCP antibodies.

Rheumatoid factor (RF) is a circulating antibody (usually IgM) which reacts with the Fc portion
of the patients own IgG

RF can be detected by either

 Rose-Waaler test: sheep red cell agglutination

 Latex agglutination test (less specific)

RF is positive in 70-80% of patients with rheumatoid arthritis, high titre levels are associated
with severe progressive disease (but NOT a marker of disease activity)

Other conditions associated with a positive RF include:

 Sjogren's syndrome (around 100%)

 Felty's syndrome (around 100%)
 infective endocarditis (= 50%)
 SLE (= 20-30%)
 systemic sclerosis (= 30%)
 general population (= 5%)
 rarely: TB, HBV, EBV, leprosy

24
Rheumatoid arthritis: complications
Rheumatoid arthritis: patients have an increased risk of IHD

A wide variety of extra-articular complications occur in patients with rheumatoid arthritis (RA):

 respiratory: pulmonary fibrosis, pleural effusion, pulmonary nodules, bronchiolitis

obliterans, methotrexate pneumonitis, pleurisy
 ocular: keratoconjunctivitis sicca (most common), episcleritis, scleritis, corneal
ulceration, keratitis, steroid-induced cataracts, chloroquine retinopathy
 osteoporosis
 ischaemic heart disease: RA carries a similar risk to type 2 diabetes mellitus
 increased risk of infections
 depression

Less common

 Felty's syndrome (RA + splenomegaly + low white cell count)

 amyloidosis

Rheumatoid arthritis: prognostic features

A number of features have been shown to predict a poor prognosis in patients with rheumatoid
arthritis, as listed below

Poor prognostic features

 rheumatoid factor positive

 poor functional status at presentation
 HLA DR4
 X-ray: early erosions (e.g. after < 2 years)
 extra articular features e.g. nodules
 insidious onset
 anti-CCP antibodies

In terms of gender there seems to be a split in what the established sources state is associated
with a poor prognosis. However both the American College of Rheumatology and the recent
NICE guidelines (which looked at a huge number of prognosis studies) seem to conclude that
female gender is associated with a poor prognosis.

25
Rheumatoid arthritis: management
The management of rheumatoid arthritis (RA) has been revolutionised by the introduction of
disease-modifying therapies in the past decade. NICE has issued a number of technology
appraisals on the newer agents and released general guidelines in 2009.

Patients with evidence of joint inflammation should start a combination of disease-modifying

drugs (DMARD) as soon as possible. Other important treatment options include analgesia,
physiotherapy and surgery.

Initial therapy

 in the 2009 NICE guidelines it is recommend that patients with newly diagnosed active
RA start a combination of DMARDs (including methotrexate and at least one other
DMARD, plus short-term glucocorticoids)

DMARDs

 methotrexate is the most widely used DMARD. Monitoring of FBC & LFTs is essential due
to the risk of myelosuppression and liver cirrhosis. Other important side-effects include
pneumonitis
 sulfasalazine
 leflunomide
 hydroxychloroquine

TNF-inhibitors

 the current indication for a TNF-inhibitor is an inadequate response to at least two

DMARDs including methotrexate
 etanercept: recombinant human protein, acts as a decoy receptor for TNF-α,
subcutaneous administration, can cause demyelination, risks include reactivation of
tuberculosis
 infliximab: monoclonal antibody, binds to TNF-α and prevents it from binding with TNF
receptors, intravenous administration, risks include reactivation of tuberculosis
 adalimumab: monoclonal antibody, subcutaneous administration

Rituximab

 anti-CD20 monoclonal antibody, results in B-cell depletion

 two 1g intravenous infusions are given two weeks apart

26
  infusion reactions are common

Abatacept

 fusion protein that modulates a key signal required for activation of T lymphocytes
 leads to decreased T-cell proliferation and cytokine production
 given as an infusion
 not currently recommend by NICE

Rheumatoid arthritis: drug side-effects

Drug Side-effects

Methotrexate Myelosuppression
Liver cirrhosis
Pneumonitis

Sulfasalazine Rashes
Oligospermia
Heinz body anaemia

Leflunomide Liver impairment

Interstitial lung disease
Hypertension

Hydroxychloroquine Retinopathy 
Corneal deposits

Prednisolone Cushingoid features

Osteoporosis
Impaired glucose tolerance
Hypertension
Cataracts

Gold Proteinuria

Penicillamine Proteinuria
Exacerbation of myasthenia gravis

Etanercept Demyelination
Reactivation of tuberculosis

27
 Drug Side-effects

Infliximab Reactivation of tuberculosis

Adalimumab Reactivation of tuberculosis

Rituximab Infusion reactions are common

Methotrexate

Methotrexate is an antimetabolite which inhibits dihydrofolate reductase, an enzyme essential

for the synthesis of purines and pyrimidines

There is an increased risk of haematological toxicity when trimethoprim is prescribed alongside

methotrexate.

Indications

 rheumatoid arthritis
 psoriasis
 acute lymphoblastic leukaemia

Adverse effects

 mucositis
 myelosuppression
 pneumonitis
 pulmonary fibrosis
 liver cirrhosis

Pregnancy

 women should avoid pregnancy for at least 3 months after treatment has stopped
 the BNF also advises that men using methotrexate need to use effective contraception
for at least 3 months after treatment

28
Prescribing methotrexate

 methotrexate is a drug with a high potential for patient harm. It is therefore important
that you are familiar with guidelines relating to its use
 methotrexate is taken weekly, rather than daily
 FBC, U&E and LFTs need to be regularly monitored. The Committee on Safety of
Medicines recommend 'FBC and renal and LFTs before starting treatment and repeated
weekly until therapy stabilised, thereafter patients should be monitored every 2-3
months'
 folic acid 5mg once weekly should be co-prescribed, taken more than 24 hours after
methotrexate dose
 the starting dose of methotrexate is 7.5 mg weekly (source: BNF)
 only one strength of methotrexate tablet should be prescribed (usually 2.5 mg)
 avoid prescribing trimethoprim or cotrimoxazole concurrently - increases risk of marrow
aplasia

29
30
Sjogren's syndrome

Sjogren's syndrome is an autoimmune disorder affecting exocrine glands resulting in dry

mucosal surfaces. It may be primary (PSS) or secondary to rheumatoid arthritis or other
connective tissue disorders, where it usually develops around 10 years after the initial onset.
Sjogren's syndrome is much more common in females (ratio 9:1). There is a marked increased
risk of lymphoid malignancy (40-60 fold)

Features

 dry eyes: keratoconjunctivitis sicca

 dry mouth
 vaginal dryness
 arthralgia
 Raynaud's, myalgia
 sensory polyneuropathy
 renal tubular acidosis (usually subclinical)

Investigation

 rheumatoid factor (RF) positive in nearly 100% of patients

 ANA positive in 70%
 anti-Ro (SSA) antibodies in 70% of patients with PSS
 anti-La (SSB) antibodies in 30% of patients with PSS
 Schirmer's test: filter paper near conjunctival sac to measure tear formation
 histology: focal lymphocytic infiltration
 also: hypergammaglobulinaemia, low C4

Management

 artificial saliva and tears

 pilocarpine may stimulate saliva production

31
Psoriatic arthropathy
A 25-year-old girl presents with a swollen first finger and wrist pain associated with a 4 month
history of generalised fatigue. She has no other symptoms including no skin changes, and no
previous medical history. Her mother suffers from psoriasis. She had the following blood tests
as part of her investigations. 

Hb125 g /l Platelets390 * 109 /l WBC14.5 * 109/l ESR78 mm/h Rheumatoid Factor Negative
Antinuclear Antibody Negative

What is the most likely diagnosis?

Whilst SLE and rheumatoid arthritis can affect females of this age group, the most likely option
is psoriatic arthritis as the patient has dactylitis and a first- degree relative with psoriasis. In
addition, rheumatoid factor and antinucleur antibody are often positive in rheumatoid arthritis,
and antinucleur antibody is predominantly positive in SLE. 

32
Gout often affects the first metatarsophalangeal joint of the first toe. 

Osteoarthritis is unlikely as the patient is young, has constitutional symptoms (fatigue), a raised
ESR and there is no mention of previous injury to the wrist or first finger.
Males and females are affected equally by psoriatic arthritis.
All patients with suspected psoriatic arthropathy should be referred to a rheumatologist

Psoriatic arthropathy correlates poorly with cutaneous psoriasis and often precedes the
development of skin lesions. Around 10-20% percent of patients with skin lesions develop an
arthropathy with males and females being equally affected

Types*

 rheumatoid-like polyarthritis: (30-40%, most common type)

 asymmetrical oligoarthritis: typically affects hands and feet (20-30%)
 sacroilitis
 DIP joint disease (10%)
 arthritis mutilans (severe deformity fingers/hand, 'telescoping fingers')

Management

 treat as rheumatoid arthritis

 but better prognosis

Notice the nail changes on this image as well

The combination of nail changes, skin changes and arthritis points to a diagnosis of psoriatic
arthropathy.

33
X-ray showing some of changes in seen in psoriatic arthropathy. Note that the DIPs are
predominately affected, rather than the MCPs and PIPs as would be seen with rheumatoid.
Extensive juxta-articular periostitis is seen in the DIPs but the changes have not yet progressed
to the classic 'pencil-in-cup' changes that are often seen.

34
This x-ray shows changes affecting both the PIPs and DIPs. The close-up images show extensive
changes including large eccentric erosions, tuft resorption and progresion towards a 'pencil-in-
cup' changes.

*Until recently it was thought asymmetrical oligoarthritis was the most common type, based on

35
data from the original 1973 Moll and Wright paper. Please see the link for a comparison of
more recent studies

Ankylosing spondylitis: features

Ankylosing spondylitis is a HLA-B27 associated spondyloarthropathy. It typically presents in
males (sex ratio 3:1) aged 20-30 years old.

Features

 typically a young man who presents with lower back pain and stiffness of insidious onset
 stiffness is usually worse in the morning and improves with exercise
 the patient may experience pain at night which improves on getting up

Clinical examination

 reduced lateral flexion

 reduced forward flexion - Schober's test - a line is drawn 10 cm above and 5 cm below
the back dimples (dimples of Venus). The distance between the two lines should
increase by more than 5 cm when the patient bends as far forward as possible
 reduced chest expansion

Other features - the 'A's 

 Apical fibrosis
 Anterior uveitis
 Aortic regurgitation
 Achilles tendonitis
 AV node block
 Amyloidosis
 and cauda equina syndrome
 peripheral arthritis (25%, more common if female)

Ankylosing spondylitis: investigation and management

36
Clinical Knowledge Summaries specifically recommend not testing for HLA-B27 in primary
care. Inflammatory markers such as CRP/ESR may also correlate with disease activity.

The anti-TNF drugs are currently only used for patients with severe ankylosing spondylitis which
has failed to respond to NSAIDs.
Ankylosing spondylitis is a HLA-B27 associated spondyloarthropathy. It typically presents in
males (sex ratio 3:1) aged 20-30 years old.

Investigation

Inflammatory markers (ESR, CRP) are typically raised although normal levels do not exclude
ankylosing spondylitis.

HLA-B27 is of little use in making the diagnosis as it is positive in:

 90% of patients with ankylosing spondylitis

 10% of normal patients

Plain x-ray of the sacroiliac joints is the most useful investigation in establishing the diagnosis.
Radiographs may be normal early in disease, later changes include:

 sacroilitis: subchondral erosions, sclerosis

 squaring of lumbar vertebrae
 'bamboo spine' (late & uncommon)
 syndesmophytes: due to ossification of outer fibers of annulus fibrosus
 chest x-ray: apical fibrosis

37
40-year-old male. There is typical appearance of bamboo spine with a single central radiodense
line related to ossification of supraspinous and interspinous ligaments which is called dagger
sign. Ankylosing is detectable in both sacroiliac joints

Ankylosing spondylitis with well formed syndesmophytes

Lateral cervical spine. Complete fusion of anterior and posterior elements in ankylosing
spondylitis, so called bamboo spine

38
Fusion of bilateral sacroiliac joints. Sacroiliitis may present as sclerosis of joint margins which
can be asymmetrical at early stage of disease, but is bilateral and symmetrical in late disease

Syndesmophytes and squaring of vertebral bodies. Squaring of anterior vertebral margins is due
to osteitis of anterior corners. Syndesmophytes are due to ossification of outer fibers of
annulus fibrosus

Spirometry may show a restrictive defect due to a combination of pulmonary fibrosis, kyphosis
and ankylosis of the costovertebral joints.

Management

The following is partly based on the 2010 EULAR guidelines (please see the link for more
details):

 encourage regular exercise such as swimming

 physiotherapy
 NSAIDs are the first-line treatment

39
  the disease-modifying drugs which are used to treat rheumatoid arthritis (such as
sulphasalazine) are only really useful if there is peripheral joint involvement
 the 2010 EULAR guidelines suggest: 'Anti-TNF therapy should be given to patients with
persistently high disease activity despite conventional treatments'
 research is ongoing to see whether anti-TNF therapies such as etanercept and
adalimumab should be used earlier in the course of the disease

Osteoarthritis: management
In an asymptomatic patient (i.e. not locking) there is no need to refer a patient with x-ray
evidence of a loose body. NICE make specific mention of this in their recent guidelines

NICE recommend co-prescribing a PPI with NSAIDs in all patients with osteoarthritis

Osteoarthritis - paracetamol + topical NSAIDs (if knee/hand) first-line

The trapeziometacarpal joint (base of thumb) is the most common site of hand osteoarthritis

Oral NSAIDs should be used second line in osteoarthritis due to their adverse effect profile
NICE published guidelines on the management of osteoarthritis (OA) in 2014

 all patients should be offered help with weight loss, given advice about local muscle
strengthening exercises and general aerobic fitness
 paracetamol and topical NSAIDs are first-line analgesics. Topical NSAIDs are indicated
only for OA of the knee or hand
 second-line treatment is oral NSAIDs/COX-2 inhibitors, opioids, capsaicin cream and
intra-articular corticosteroids. A proton pump inhibitor should be co-prescribed with
NSAIDs and COX-2 inhibitors. These drugs should be avoided if the patient takes aspirin
 non-pharmacological treatment options include supports and braces, TENS and shock
absorbing insoles or shoes
 if conservative methods fail then refer for consideration of joint replacement

What is the role of glucosamine?

 normal constituent of glycosaminoglycans in cartilage and synovial fluid

 a systematic review of several double blind RCTs of glucosamine in knee osteoarthritis
reported significant short-term symptomatic benefits including significantly reduced
joint space narrowing and improved pain scores
 more recent studies have however been mixed
 the 2008 NICE guidelines suggest it is not recommended

40
  a 2008 Drug and Therapeutics Bulletin review advised that whilst glucosamine provides
modest pain relief in knee osteoarthritis it should not be prescribed on the NHS due to
limited evidence of cost-effectiveness

The presence of Heberden's nodes and thumb symptoms is highly suggestive of osteoarthritis.

Osteoarthritis: x-ray changes

X-ray changes of osteoarthritis

 decrease of joint space

 subchondral sclerosis
 subchondral cysts
 osteophytes forming at joint margins

Periarticular erosions are seen in rheumatoid arthritis.

Rheumatoid arthritis: x-ray changes

Juxta-articular osteoporosis would point towards a diagnosis of rheumatoid arthritis (RA). Loss
of joint space is common in both RA and osteoarthritis

Early x-ray findings

 loss of joint space

 juxta-articular osteoporosis
 soft-tissue swelling

Late x-ray findings

 periarticular erosions

41
  subluxation

Raynaud's
Raynaud's disease (i.e. primary) presents in young women with bilateral symptoms

A 31-year-old woman presents as her fingers intermittently turn white and become painful. She
describes the fingers first turning white, then blue and finally red. This is generally worse in the
winter months but it is present all year round. Wearing gloves does not help. Clinical
examination of her hands, other joints and skin is unremarkable.

Raynaud's phenomena may be primary (Raynaud's disease) or secondary (Raynaud's

phenomenon) 
Raynaud's disease typically presents in young women (e.g. 30 years old) with symmetrical
attacks

Factors suggesting underlying connective tissue disease

 onset after 40 years

 unilateral symptoms

42
  rashes
 presence of autoantibodies
 features which may suggest rheumatoid arthritis or SLE, for example arthritis or
recurrent miscarriages
 digital ulcers, calcinosis
 very rarely: chilblains

Secondary causes

 connective tissue disorders: scleroderma (most common), rheumatoid arthritis, SLE

 leukaemia
 type I cryoglobulinaemia, cold agglutinins
 use of vibrating tools
 drugs: oral contraceptive pill, ergot
 cervical rib

A history of recurrent miscarriages could indicate systemic lupus erythematous or anti-

phospholipid syndrome. Chilblains (pernio) are itchy, painful purple swellings which occur on
the fingers and toes after exposure to the cold. They are occasionally associated with
underlying connective tissue disease but this is rare

Management

 first-line: calcium channel blockers e.g. nifedipine

 IV prostacyclin infusions: effects may last several weeks/months

43
Reactive arthritis

Urethritis + arthritis + conjunctivitis = reactive arthritis

Reactive arthritis is one of the HLA-B27 associated seronegative spondyloarthropathies. It

encompasses Reiter's syndrome, a term which described a classic triad of urethritis,
conjunctivitis and arthritis following a dysenteric illness during the Second World War. Later
studies identified patients who developed symptoms following a sexually transmitted infection
(post-STI, now sometimes referred to as sexually acquired reactive arthritis, SARA).

Reactive arthritis is defined as an arthritis that develops following an infection where the
organism cannot be recovered from the joint.

Features

 typically develops within 4 weeks of initial infection - symptoms generally last around 4-
6 months
 arthritis is typically an asymmetrical oligoarthritis of lower limbs
 dactylitis
 symptoms of urethritis
 eye: conjunctivitis (seen in 50%), anterior uveitis
 skin: circinate balanitis (painless vesicles on the coronal margin of the prepuce),
keratoderma blenorrhagica (waxy yellow/brown papules on palms and soles)

Around 25% of patients have recurrent episodes whilst 10% of patients develop chronic disease

44
'Can't see, pee or climb a tree'

Keratoderma blenorrhagica

Epidemiology

 post-STI form much more common in men (e.g. 10:1)

 post-dysenteric form equal sex incidence

The table below shows the organisms that are most commonly associated with reactive
arthritis:

Post-dysenteric form Post-STI form

Shigella flexneri Chlamydia  trachomatis

Salmonella typhimurium
Salmonella enteritidis
Yersinia enterocolitica
Campylobacter

Management

 symptomatic: analgesia, NSAIDS, intra-articular steroids

 sulfasalazine and methotrexate are sometimes used for persistent disease
 symptoms rarely last more than 12 months

45
Temporal arteritis

A 68-year-old female presents to her GP with a two week history of intermittent headaches and
lethargy. Blood tests reveal the following:

ESR = 67 mm/hr

This is a classic history of temporal arteritis. Treatment should be started immediately with high
dose steroids (e.g. prednisolone 1mg/kg/day) to reduce the chance of visual loss
Temporal arteritis is large vessel vasculitis which overlaps with polymyalgia rheumatica (PMR).
Histology shows changes which characteristically 'skips' certain sections of affected artery
whilst damaging others.

Features

 typically patient > 60 years old

 usually rapid onset (e.g. < 1 month)
 headache (found in 85%)
 jaw claudication (65%)
 visual disturbances secondary to anterior ischemic optic neuropathy

46
  tender, palpable temporal artery
 features of PMR: aching, morning stiffness in proximal limb muscles (not weakness)
 also lethargy, depression, low-grade fever, anorexia, night sweats

Investigations

 raised inflammatory markers: ESR > 50 mm/hr (note ESR < 30 in 10% of patients). CRP
may also be elevated
 temporal artery biopsy: skip lesions may be present
 note creatine kinase and EMG normal

Treatment

 high-dose prednisolone - there should be a dramatic response, if not the diagnosis

should be reconsidered
 urgent ophthalmology review. Patients with visual symptoms should be seen the same-
day by an ophthalmologist. Visual damage is often irreversible

Polymyalgia rheumatic

Pathophysiology

 overlaps with temporal arteritis

 histology shows vasculitis with giant cells, characteristically 'skips' certain sections of
affected artery whilst damaging others
 muscle bed arteries affected most in polymyalgia rheumatica

47
Features

 typically patient > 60 years old

 usually rapid onset (e.g. < 1 month)
 aching, morning stiffness in proximal limb muscles (not weakness)
 also mild polyarthralgia, lethargy, depression, low-grade fever, anorexia, night sweats

Investigations

 ESR > 40 mm/hr

 note CK and EMG normal
 reduced CD8+ T cells

Treatment

 prednisolone e.g. 15mg/od - dramatic response.

Marfan's syndrome

48
Marfan's syndrome is an autosomal dominant connective tissue disorder. It is caused by a
defect in the fibrillin-1 gene on chromosome 15 and affects around 1 in 3,000 people.

Features

 tall stature with arm span to height ratio > 1.05

 high-arched palate
 arachnodactyly
 pectus excavatum
 pes planus
 scoliosis of > 20 degrees
 heart: dilation of the aortic sinuses (seen in 90%) which may lead to aortic aneurysm,
aortic dissection, aortic regurgitation, mitral valve prolapse (75%),
 lungs: repeated pneumothoraces
 eyes: upwards lens dislocation (superotemporal ectopia lentis), blue sclera, myopia
 dural ectasia (ballooning of the dural sac at the lumbosacral level)

Rt foot Pes Planus

49
The life expectancy of patients used to be around 40-50 years. With the advent of regular
echocardiography monitoring and beta-blocker/ACE-inhibitor therapy this has improved
significantly over recent years. Aortic dissection and other cardiovascular problems remain the
leading cause of death however.

Systemic sclerosis

Systemic sclerosis is a condition of unknown aetiology characterised by hardened, sclerotic skin

and other connective tissues. It is four times more common in females

There are three patterns of disease:

Limited cutaneous systemic sclerosis

 Raynaud's may be first sign

 scleroderma affects face and distal limbs predominately
 associated with anti-centromere antibodies
 a subtype of limited systemic sclerosis is CREST syndrome: Calcinosis, Raynaud's
phenomenon, oEsophageal dysmotility, Sclerodactyly, Telangiectasia

50
Diffuse cutaneous systemic sclerosis

 scleroderma affects trunk and proximal limbs predominately

 associated with scl-70 antibodies
 hypertension, lung fibrosis and renal involvement seen
 poor prognosis

Scleroderma (without internal organ involvement)

 tightening and fibrosis of skin

 may be manifest as plaques (morphoea) or linear

51
Please look at the hands of this 50-year-old lady. She complains of tight, stiff fingers that turn
white in the cold.
This patient has Sclerodactyly and Raynaud's phenomenon. Telangiectasia can also be seen on
the hands. She therefore has the RST of CREST syndrome, or more accurately limited cutaneous
systemic sclerosis.

52
Antibodies

 ANA positive in 90%

 RF positive in 30%
 anti-scl-70 antibodies associated with diffuse cutaneous systemic sclerosis
 anti-centromere antibodies associated with limited cutaneous systemic sclerosis

Fibromyalgia

53
A recent JAMA paper supported the use of anti-depressants in fibromyalgia

Treatment of fibromyalgia syndrome with antidepressants: a meta-analysis; 2009 Jan

14;301(2):198-209
Fibromyalgia is a syndrome characterised by widespread pain throughout the body with tender
points at specific anatomical sites. The cause of fibromyalgia is unknown.

Epidemiology

54
  women are 10 times more likely to be affected
 typically presents between 30-50 years old

Features

 chronic pain: at multiple site, sometimes 'pain all over'

 lethargy
 sleep disturbance, headaches, dizziness are common

Diagnosis is clinical and sometimes refers to the American College of Rheumatology 

classification criteria which lists 9 pairs of tender points on the body. If a patient is tender in at
least 11 of these 18 points it makes a diagnosis of fibromyalgia more likely

The management of fibromyalgia is often difficult and needs to be tailored to the individual
patient. A psychosocial and multidisciplinary approach is helpful. Unfortunately there is
currently a paucity of evidence and guidelines to guide practice. The following is partly based
on consensus guidelines from the European League against Rheumatism (EULAR) published in
2007 and also a BMJ review in 2014.

 explanation
 aerobic exercise: has the strongest evidence base
 cognitive behavioural therapy
 medication: pregabalin, duloxetine, amitriptyline

Paget's disease of the bone

Paget's disease - old man, bone pain, raised ALP

Calcium=2.20 mmol /lPhosphate=0.8 mmol/ lALP=890 u/L

The normal calcium and phosphate combined with a raised alkaline phosphate points to a
diagnosis of Paget's
Paget's disease is a disease of increased but uncontrolled bone turnover. It is thought to be
primarily a disorder of osteoclasts, with excessive osteoclastic resorption followed by increased
osteoblastic activity. Paget's disease is common (UK prevalence 5%) but symptomatic in only 1
in 20 patients

Predisposing factors

 increasing age
 male sex
 northern latitude

55
  family history

Clinical features - only 5% of patients are symptomatic

 bone pain (e.g. pelvis, lumbar spine, femur)

 classical, untreated features: bowing of tibia, bossing of skull
 raised alkaline phosphatase (ALP) - calcium* and phosphate are typically normal
 skull x-ray: thickened vault, osteoporosis circumscripta

Indications for treatment include bone pain, skull or long bone defo rmity, fracture,
periarticular Paget's

 bisphosphonate (either oral risedronate or IV zoledronate)

 calcitonin is less commonly used now

Complications

 deafness (cranial nerve entrapment)

 bone sarcoma (1% if affected for > 10 years)
 fractures
 skull thickening
 high-output cardiac failure

56
The radiograph demonstrates marked thickening of the calvarium. There are also ill-defined
sclerotic and lucent areas throughout. These features are consistent with Paget's disease.

Pelvic x-ray from an elderly man with Paget's disease. There is a smooth cortical expansion of
the left hemipelvic bones with diffuse increased bone density and coarsening of trabeculae.

Isotope bone scan from a patient with Paget's disease showing a typical distribution in the
spine, asymmetrical pelvic disease and proximal long bones.

*usually normal in this condition but hypercalcaemia may occur with prolonged immobilization

Dactylitis
A 'sausage-shaped' digit is a classical description of dactylitis. It would be unusual for gout to
affect the middle toe, the vast majority of cases occur in the first metatarsophalangeal joint.

57
The lack of systemic upset, length of history and confined erythema go against a diagnosis of
septic arthritis (e.g. linked to diabetes).

Dactylitis is not a feature of rheumatoid arthritis.

Dactylitis describes the inflammation of a digit (finger or toe).

Causes include:

 spondyloarthritis: e.g. Psoriatic and reactive arthritis

 sickle-cell disease
 other rare causes include tuberculosis, sarcoidosis and syphilis

Takayasu's arteritis
Takayasu's arteritis is a large vessel vasculitis. It typically causes occlusion of the aorta and
questions commonly refer to an absent limb pulse. It is more common in females and Asian
people

Features

 systemic features of a vasculitis e.g. malaise, headache

 unequal blood pressure in the upper limbs
 carotid bruit
 intermittent claudication
 aortic regurgitation (around 20%)

58
 Angiography showing multiple stenoses in the branches of the aorta secondary to Takayasu's
arteritis

Associations

 renal artery stenosis

Management

 steroids

59