Systemic Sclerosis

Question 1

Systemic Sclerosis

Answer 1

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

Question 2

Limited Cutaneous Systemic Sclerosis

Answer 2

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

Late Cx of CREST = Pulmonary HTN

Sclerodactyly is a localized thickening and tightness of the skin of the fingers or toes. Sclerodactyly often leads to ulceration of the skin of the distal digits and is commonly accompanied by atrophy of the underlying soft tissues.

Question 3

Diffuse Cutaneous Systemic Sclerosis

Answer 3

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

Question 4

Scleroderma (without internal organ involvement)

Answer 4

Scleroderma (without internal organ involvement)

• tightening and fibrosis of skin
• may be manifest as plaques (morphoea) or linear

Question 5

Systemic Sclerosis - Antibodies

Answer 5

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

Question 6

Scleroderma Renal Crisis

Answer 6

‘A 66-year-old Caucasian female presents with 3 week history of worsening headache and 2 day history of shortness of breath. She reports disturbed sleeping at night due to an inability to lie down, due to her shortness of breath. She has no known past medical history and drug history. On examination, you note bilateral splinter haemorrhages, 4 on the right and 2 on the left, with calcium deposits distally and black spots in the pulp of the fingers. Perioral skin puckering is also noted. Cardiovascular examination is unremarkable, chest examination reveals bilateral coarse inspiratory crackles. Neurological examination is unremarkable except fundoscopy revealing papilloedema, cotton wool spots and flame haemorrhages. The patient is apyrexic, Sats 95% on 2 litres, respiratory rate 24/min, blood pressure 195/115 mmHg, HR 90/min and regular. Chest x-ray demonstrates bilateral pleural effusion with bilateral alveolar shadowing. What is the most important immediate management?’

This patient presents with signs of cutaenous manifestations of systemic sclerosis, grade 4 hypertensive retinopathy and heart failure. She is is scleroderma renal crisis (SRC), an emergency that if left untreated, is fatal. The optimal drug of choice is an ACE inhibitor, preferably captopril, which has been trialed with the greatest experience, but other ACEi are also likely to be beneficial. In a 15 year prospective cohort, one year survival increased from 15% to 76% with the use of ACEi against other anti-hypertensives1. Steroids should be strictly avoided in SRC, they increase the risk of SRC prior to the event and may exacerbate SRC in the acute setting. Renal dialysis may be required in patients who progress to end-stage renal failure despite ACEi treatments.

Question 7

Raynaud’s 2dry to Systemic Sclerosis: Example Question

Answer 7

A 47-year-old lady presented with a three-week history of pain in her fingers. She had noticed her hands were getting extremely cold when she went outside and turned a ‘funny colour’. When she came back inside her hands were very painful as they began to warm up. She had managed in the past by wearing gloves outside but now had ulcers on her fingertips which she had never experienced before. She also complained of epigastric pain and had longstanding shortness of breath.

Her past medical history included pulmonary fibrosis and hypertension. Her medications included propranolol, amlodipine, simvastatin and omeprazole.

On examination the skin over her hands was dry and shiny and there was severe digital ulceration on three fingertips of the left hand. There was no exudate or erythema. The fingertips were dusky in colour and extremely tender. The skin over the upper arms and chest appeared normal. On auscultation of the lungs there were fine bibasal inspiratory crepitations which did not alter in character upon coughing. Heart sounds were normal with no added murmurs. There was a left ventricular heave

Which of the following is the most appropriate management plan for this lady?

Start flucloxacillin and stop all anti-hypertensive medications
Educate this lady about the use of gloves and hand-warmers and increase her amlodipine dose
Stop amlodipine and refer for an urgent dermatology assessment > 	Stop propranolol and admit for an iloprost infusion
Start high dose oral prednisolone

This patient has secondary Raynauds associated with an underlying diagnosis of Limited Systemic Sclerosis. Her disease is ‘limited’ as opposed to ‘diffuse’ as she does not have skin changes proximal to the elbows. She clearly has systemic involvement with pulmonary fibrosis and oesophageal dysmotility (she has epigastric pain and is taking omeprazole). Other features that were not mentioned in the question but may be present in such patients include telangiectasia, typically over mucosal surfaces, a ‘beak-like’ nose and microstomia, calcinosis and renal impairment.

Severe digital ulceration in such patients can be treated with infusion of a prostacyclin analogue such as iloprost. Prompt treatment is required to avoid gangrene and loss of digits. Drugs such as beta blockers and the oral contraceptive pill can exacerbate Raynauds phenomenon by causing vascular spasm and should therefore be avoided.

There is no indication for flucloxacillin if the ulcers are not infected.

Gloves and hand-warmers can be very helpful for patients with Raynauds phenomenon. Calcium channel blockers such as amlodipine and nifidepine cause vasodilation in peripheral arterioles are also used to treat Raynauds phenomenon. However, if there is severe ulceration admission for an iloprost infusion is required.

Question 8

Raynaud’s

Answer 8

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

Question 9

Raynaud’s - Factors suggesting underlying connective tissue disease

Answer 9

Factors suggesting underlying connective tissue disease
onset after 40 years
unilateral symptoms
rashes
presence of autoantibodies
features which may suggest rheumatoid arthritis or SLE, for example arthritis or recurrent miscarriages
digital ulcers, calcinosis
very rarely: chilblains

Question 10

Raynaud’s - Secondary Causes

Answer 10

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

Question 11

Raynaud’s - Mx

Answer 11

Management
first-line: calcium channel blockers e.g. nifedipine
IV prostacyclin infusions e.g. Ilioprost: effects may last several weeks/months

Question 12

Differentiating between Limited and Diffuse Systemic Sclerosis

Answer 12

Systemic sclerosis (SS) is a fairly clear answer when presented with a combination of sclerodactyly, calcinosis, perioral puckering and gastro-oesophageal reflux symptoms in a middle-aged female.

The main differentials are whether this represents diffuse cutaneous, limited cutaneous or systemic sclerosis sine scleroderma.

The latter describes patients with systemic involvement and possible Raynauds phenomenon in the absence of other cutaneous manifestations with detection of SS autoantibodies.

SS can be described generally as diffuse when skin proximal to the distal forearm is involved, such as the elbow, thorax or abdomen.

Note that both limited and diffuse cutaneous SS have extracutaneous involvement: however, patients with diffuse cutaneous SS are more likely to develop significant renal, lung and cardiac disease.

Autoantibodies are useful in confirming the subtype of SS and predict extracutaneous involvement but negative results do not rule out SS.

Dysphagia and some lung fibrosis occurs in both limited and diffuse scleroderma.

Diffuse scleroderma is characterised by lesions proximal to the elbow, trunk and face (limited can have some facial involvement).

Anti-centromere antibodies are associated with limited cutaneous SS
Anti-Scl 70 with diffuse SS and lung involvement1
Anti-RNA polymerase III to those at high risk of scleroderma renal crisis
Anti-U3-RNP to those at high risk of pulmonary hypertension
Anti-PM-Scl to those at high risk of SS associated myositis

Question 13

Limited Systemic Sclerosis: Diagnosis - Example Question

Answer 13

A 41-year-old woman presents with tightening of fingers, mild difficulty swallowing, and mild shortness of breath on exertion. She takes pantoprazole for reflux. On examination there is tightening of skin in her fingers, however the rest of the skin is normal. Her joints are not inflamed. The rest of her examination was normal (including chest examination). Her chest X-ray is also normal. There is mild decrease in DLCO on lung function tests. Which of the following antibodies are indicative of the underlying diagnosis?

	Anti-Scl-70 antibody
	Anti-dsDNA antibody
	Rh factor antibody
	> Anti-centromere antibody
	Anti-Jo-1 antibody

The underlying diagnosis is limited scleroderma. Limited scleroderma has tightened hard skin below the elbows. Dysphagia and some lung fibrosis occurs in both limited and diffuse scleroderma. Limited scleroderma is associated with anti-centromere antibody with Anti-scl-70 antibody associated with diffuse scleroderma. Diffuse scleroderma is characterised by lesions proximal to the elbow, trunk and face (limited can have some facial involvement). Limited scleroderma has a 90% 5-year survival, diffuse scleroderma 70% 5-year survival. In the past, renal crises were the most common cause of death in patients with scleroderma. Aggressive treatment with blood pressure lowering drugs, particularly those known as ACE inhibitors, is proving to be successful in reducing this risk.

Anti-dsDNA and Rh factor are indicative of SLE an RA/Sjogrens/others, but there is no evidence of arthritis or cutaneous rashes. Anti-Jo-1 antibody is a marker of polymyositis.

Question 14

Cutaneous manifestations of Limited SS - diagnosis made just from looking at the hands!

Answer 14

Eg ‘Please look at the hands of this 50-year-old lady. She complains of tight, stiff fingers that turn white in the cold’

SEE PASSMED HANDS PHOTO LIMITED SS

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.

Question 15

Systemic SS and Steroids

Answer 15

Steroid use is known to precipitate scleroderma renal crisis!

Example patient:
A 35-year-old lady with diffuse systemic sclerosis attends the rheumatology clinic. She has had worsening arthralgia over the last 2 months, mainly in the hands and feet. She does not complain of any other symptoms.

On examination her blood pressure is 161/94 mmHg, her heart rate is 90 beats per minute and her oxygen saturations are 96% on room air. She has sclerodactyly and tender small joints of the hands and feet with mild swelling. The hands are pale and cool. Her chest is clear.

Her blood tests are as follows:

Hb 110 g/l Na+ 136 mmol/l Bilirubin 5 µmol/l
Platelets 210 * 109/l K+ 4.7 mmol/l ALP 90 u/l
WBC 10 * 109/l Urea 5 mmol/l ALT 21 u/l
Neuts 7 * 109/l Creatinine 89 µmol/l γGT 30 u/l
Lymphs 2.5 * 109/l ESR 99 mm/h Albumin 32 g/l

Which drug should be used with caution in this patient?

	Tacrolimus
	Azathioprine
	Methotrexate
	Mycophenolate mofetil
>	Prednisolone

Steroid use is known to precipitate scleroderma renal crisis and this is a patient who already has hypertension. Azathioprine, mycophenolate mofetil, tacrolimus and methotrexate are all immunosuppressive agents which may be used in rheumatological conditions, though methotrexate may cause additional pulmonary fibrosis.

Question 16

Sclerodermic Renal Crisis: Example Question

Answer 16

A 67-year-old female presented to the accident and emergency department with severe headache and shortness of breath for the last six hours followed by seizures which occurred twice during the last hour.

The patient is a known case of diffuse cutaneous systemic sclerosis diagnosed two years ago and she is on steroids and cyclophosphamide.

On examination, she looks ill, agitated and dyspnoeic. Her pulse rate is 100 beats per minute, regular and her blood pressure is 220/110 mmHg.

Her JVP is raised, there is a gallop rhythm and bilateral basal crackles. There is lower limb oedema and brisk reflexes.

Fundoscopy showed grade 3 hypertensive retinopathy.

Investigations done two weeks previously showed:

Serum sodium	140 mmol/L
Serum potassium	5.7 mmol/L
Serum urea	17 mmol/L
Serum creatinine	250 mol/L
Urinalysis	protein ++, blood ++

What is the most appropriate immediate treatment to lower her blood pressure?

	IV sodium nitroprusside
	IV labetalol
>	Oral ACE inhibitor
	IV hydralazine
	Nitrate infusion

This patient has developed scleroderma renal crisis which presents as malignant hypertension, heart failure and rapid deterioration of renal function progressing to acute renal failure.

This hypertensive emergency should be managed with gradual reduction of blood pressure at a rate of 10-15 mmHg per day with an oral ACE inhibitor as the pathology of scleroderma renal crisis is vasospasm.

IV sodium nitroprusside and IV labetalol should be avoided as they lead to sudden reduction of blood pressure and renal hypoperfusion that leads to acute tubular necrosis, making the already deranged renal function even worse.

Indeed, this patient requires ICU admission for management of her heart failure and acute renal failure.

Question 17

Sclerodermic Renal Crisis

Answer 17

Presents as malignant hypertension, heart failure and rapid deterioration of renal function progressing to acute renal failure.

This hypertensive emergency should be managed with gradual reduction of blood pressure at a rate of 10-15 mmHg per day with an oral ACE inhibitor as the pathology of scleroderma renal crisis is vasospasm.

IV sodium nitroprusside and IV labetalol should be avoided as they lead to sudden reduction of blood pressure and renal hypoperfusion that leads to acute tubular necrosis, making the already deranged renal function even worse.

Question 18

Limited Systemic Sclerosis (CREST) Complication

Answer 18

MALABSORPTION 2dry to bacterial overgrowth of the sclerosed SI

Question 19

Systemic Sclerosis - 3 patterns

Answer 19

1) Limited
- subtype = CREST (Calcinosis, Raynauds, Oeosphageal dysmotility, Sclerodactyly, Telangiectasia)
- Scleroderma affects face and distal limbs predominantly
- Raynaud’s may be first sign

2) Systemic
- Scleroderma affects trunk and proximal limbs predominantly
- HTN, Lung fibrosis, Renal involvement
- Poor prognosis

3) Scleroderma = without internal organ involvement
- tightening and fibrosis of the skin
- may manifest as plaques (morphoea) or linear

NB All are 4 x more common in F

Question 20

Sclerodermic Renal Crisis - HTN: Example Question

Answer 20

A 59-year-old lady comes to the blood pressure clinic with accelerated hypertension which isn’t responding to lifestyle modifications.

The patient denies any headaches or blurred vision. However, she admits to a chronic cough and frequently passes pale, loose stools. She frequently gets cold hands and tells you they go red, white and then blue in the winter.

On examination, she is a thin lady with a blood pressure of 190/100 mmHg and a heart rate of 68 beats per minute. Although her nails are a normal colour she has tight, shiny skin over her hands. An ECG shows sinus rhythm.

Hb	106 g/l
Platelets	451 * 109/l
WBC	8.9 * 109/l
Na+	136 mmol/l
K+	4.9 mmol/l
Urea	7.1 mmol/l
Creatinine	174 µmol/l

Which of the following is the most appropriate initial therapy?

	Bisoprolol
	Candesartan
	> Captopril
	Indapamide
	Amlodipine

The patient describes Raynaud’s phenomenon and mentions bowel and possibly lung involvement along with tight skin. This could point towards scleroderma. In this case, then, the raised creatinine and hypertension are suggestive of a scleroderma renal crisis. The first line treatment, in this case, is an ACE inhibitor.

Amlodipine would be the antihypertensive of choice if this were essential hypertension.

Question 21

Sclerodermic Renal Crisis - Example Question

Answer 21

You are the medical doctor on an acute medical admissions unit. A 56-year old female with hypertension, pulmonary fibrosis and a recent diagnosis of Raynaud’s phenomenon presents with generally feeling unwell. On further questioning she also reports dysphagia for the past few months for which she is awaiting investigations under the gastroenterology team at your hospital. She is currently only on amlodipine 5mg od.

Her observations are: temperature 36.4°C, pulse 88/min, blood pressure 172/88 mmHg, respiratory rate 14/min, sats 100% on room air. Her chest is clear and abdomen soft, non-tender. Blood tests reveal an acute kidney injury with: sodium 141 mmol/l, potassium 4.6 mmol/l, urea 27 mmol/l, creatinine 320 µmol/l (her GP notes state she had a normal renal function from a routine blood test 1 month ago).

What is the most appropriate treatment at this stage?

	Fluids
	Stat 5mg amlodipine
	> Stat angiotensin-converting enzyme inhibitor (ACE-i)
	Haemodialysis
	Haemofiltration

This lady has features of diffuse cutaneous systemic sclerosis - she has Raynaud’s phenomenon, pulmonary fibrosis and dysphagia. Her current presentation is that of scleroderma renal crisis. This is a medical emergency and treatment should be administered as soon as possible. The most appropriate treatment initially would be an ACE-i with a consideration for dialysis and renal transplantation if required.

Question 22

Complications of GI Systemic Sclerosis - Example Question

Answer 22

A 68-year-old Indian patient presents to the emergency department with facial tetany, muscle cramps and paraesthesia of her fingers and toes. This is her second admission with similar symptoms. Her past medical history includes diffuse cutaneous systemic sclerosis with gastrointestinal, cutaneous and pulmonary manifestations. She was also diagnosed with vitamin D deficiency two years ago and receives regular vitamin D supplements. Her blood tests are as follows:

Hb	124 g/l
WBC	8.0 * 109/l
Na+	141 mmol/l
K+	4.3 mmol/l
Urea	6.5 mmol/l
Creatinine	90 µmol/l
CRP	15 mg/l
Corrected calcium	1.68 mmol/l
Phosphate	1.4 mmol/l
Magnesium	0.28 mmol/l
PTH	2 pmol/L (normal range = 8.5-12)
Amylase	14 u/l

Her symptoms improve with intravenous calcium replacement and intravenous magnesium replacement, correcting both electrolytes to within normal range. What is the underlying cause for these metabolic disturbances in this patient?

	> Hypomagnesaemia
	Primary hypoparathyroidism
	Insufficient vitamin D supplementation
	Chronic kidney failure
	Chronic pancreatitis

This complex picture investigates the underlying cause of hypomagnesaemia and hypocalcaemia in a patient with significant GI disease. With regular vitamin D supplementation, it is unlikely this is the cause. Her renal function is also within normal range. Although her parathyroid hormone levels are low, the likely underlying cause is due to insufficient magnesium absorption due to GI systemic sclerosis, which results in reduces parathyroid hormone release. There is nothing in the history to suggest a primary hypoparathyroidism or chronic pancreatitis.

Question 23

Scleroderma and Malabsorption

Answer 23

Malabsorption is a v common Cx of Scleroderma

Bloods:

• Low vitamin e.g. B12, Folate
• Low nutrients e.g. Iron
• Low protein e.g. Albumin
• Low magnesium > Low calcium

Question 24

Sclerodermic Renal Crisis

Answer 24

Eg patient presents with signs of cutaenous manifestations of systemic sclerosis, grade 4 hypertensive retinopathy and heart failure = scleroderma renal crisis (SRC), an emergency that if left untreated, is fatal.

The optimal drug of choice is an ACE inhibitor, preferably captopril, which has been trialed with the greatest experience, but other ACEi are also likely to be beneficial. In a 15 year prospective cohort, one year survival increased from 15% to 76% with the use of ACEi against other anti-hypertensives.

Steroids should be strictly avoided in SRC, they increase the risk of SRC prior to the event and may exacerbate SRC in the acute setting.

Renal dialysis may be required in patients who progress to end-stage renal failure despite ACEi treatments.

Question 25

Raynauds in CREST - Mx

Answer 25

Severe digital ulceration in such patients can be treated with infusion of a prostacyclin analogue such as iloprost. Prompt treatment is required to avoid gangrene and loss of digits.

Drugs such as beta blockers and the oral contraceptive pill can exacerbate Raynauds phenomenon by causing vascular spasm and should therefore be avoided.

There is no indication for Abx unless ulcers are infected.

Gloves and hand-warmers can be very helpful for patients with Raynauds phenomenon.

Calcium channel blockers such as amlodipine and nifidepine cause vasodilation in peripheral arterioles are also used to treat Raynauds phenomenon. However, if there is severe ulceration admission for an iloprost infusion is required.

Question 26

Systemic Sclerosis - Assoc antibodies

Answer 26

Anti-centromere antibodies are associated with limited cutaneous SS
Anti-Scl 70 with diffuse SS and lung involvement
Anti-RNA polymerase III to those at high risk of scleroderma renal crisis
Anti-U3-RNP to those at high risk of pulmonary hypertension
Anti-PM-Scl to those at high risk of SS associated myositis

Question 27

Sclerodermic Renal Crisis

Answer 27

MALIGNANT HTN (High BP, Hypertensive Retinopathy)
HEART FAILURE
ACUTE RENAL FAILURE

= Emergency

This hypertensive emergency should be managed with gradual reduction of blood pressure at a rate of 10-15 mmHg per day with an oral ACE inhibitor as the pathology of scleroderma renal crisis is vasospasm.

ICU admission for management of heart failure and acute renal failure.