Scleroderma

Question 1

What can systemic sclerosis be categorised into?

Answer 1

Limited cutaneous systemic sclerosis (more common, 55%)

• characterized by distal (face, neck, and hands), but not proximal, skin thickening; it is usually unaccompanied by internal organ fibrosis
• CREST syndrome: calcinosis, raynauds, esophageal dysmotility, sclerodactyly (skin tightening), telangiectasia
• Raynauds take years to occur
• Gradual onset skin changes limited to upper limbs, face
• Clinically significant ILD less frequent (<20%), cardiac and renal disease rare
• Anti-centromere ab; CREST

Diffuse cutaneous systemic sclerosis (less common 35%)
- characterized by extensive distal and proximal skin thickening (chest, abdomen, and arms proximal to wrists) and is commonly accompanied by internal organ fibrosis + ILD
- Raynauds - short history
- Rapid onset skin changes causing contractures
- Skin of trunk and proximal limbs
- Tendon friction rubs
Constitutional symptoms
- Early onset internal organ involvement: ILD 40%, renal crisis 10%
- Anti-Scl-70 ab: ILD
- Anti RNA polymerase I, III antibodies: scleroderma renal crisis
- ANA with nucleolar pattern

Pulmonary artery hypertension ~10% in both subtypes.

Question 2

Autoantibodies in scleroderma

Answer 2

• Anti-centromere: limited SSc, Pulmonary HTN
• Topoisomerase I = SCL70 = ILD
• RNA polymerase III = severe renal and skin
• anti Scl 70: speckled ANA, diffuseSc, ILD
• RNA polymease III: fine speckled nucleolar, diffuse Sc, associated with renal crisis, skin involvement and malignancy within 2-5 years of diagnosis
• anti-centromere: centromere pattern, limited SC, protection from ILD/renal disease, causes more PAH and oesophageal disease

U1-RNP: Limited + diffuse, overlap features

PM-SCL, limited + diffuse, myositis overlaps

Th/T0: limited + diffuse, associated with PAH and worse prognosis

Question 3

What is the leading cause of death in scleroderma?

Answer 3

Cardiopulmonary manifestations - pulmonary fibrosis and pulmonary arterial hypertension (PAH has worst prognosis)

Previously would be scleroderma renal crisis but due to ACEi this has now improved survival

The most common cause of death in systemic sclerosis is respiratory involvement: interstitial lung disease and pulmonary arterial hypertension

Question 4

What is the most common ILD in scleroderma?

Answer 4

Non specific interstitial pneumonitis > usual interstitial pneumonitis

Usual Interstitial Pneumonia (UIP): subpleural reticulation, apical-basal gradient, traction bronchiectasis, honeycombing

Non specific interstitial pneumonia: ground glass change, apical basal gradient, subpleural sparing, traction bronchectaisis

Question 5

What is the follow-up for early ILD?

Answer 5

Patients with early diffuse SSc with ILD should be monitored with spirometry and DLCO every 3-4 months for 3-5 years after disease onset then yearly.
No advantage in serial HRCT if PFTs are stable.

Question 6

What are the high risk phenotype for ILD?

Answer 6

• Early diffuse + anti-SCL70

- Early diffuse + elevated CRP

Question 7

Treatment for scleroderma ILD

Answer 7

• 1st line: mycophenolate (purine synthesis inhibitors)
• Severe or progressive disease unresponsive to mycophenolate: cyclophosphamide for 6-12 months followed by mycophenolate OR azathioprine

Other:

• Nintedanib: tyrosine kinase inhibitor with antifibriotic and anti-inflammatory effects
• Pirfenidone
• Rituximab
• Tocilizumab: IL6
• Lung transplant
• Autologous stem cell transplant

Question 8

Cutaneous findings of scleroderma

Answer 8

• Thickening and hardening of the skin
• Sclerodactyly
• Painful ischaemic digital ulcers with atrophy and necrotic spots
• Microstoma - small sized mouth

Question 9

Muscle involvement in scleroderma.

Answer 9

• Arthralgia, myalgia, fatigue
• Later in disease, fibrosis of the periarticular structures lead to joint pain, immobility and contractures especially in fingers and extremities
• Fibrosis of tendons associated with palpable and/or audible deep tendon friction rubs, occur more commonly in diffuse and may indicate internal organ invovement.

Question 10

Raynaud phenomenon

Answer 10

Raynaud phenomenon (sequential white, blue, and red color changes in the digits precipitated by cold or stress) occurs in almost all patients with SSc. Raynaud phenomenon is initially transient and reversible; later, structural changes develop within small blood vessels, resulting in permanently impaired flow that produces acrocyanosis, digital pitting, and/or ulcerations.

> 50% have a digital ulcer at some point

Question 11

Treatment for raynaud’s phenomenon

Answer 11

Non pharmacological

• Keep warm
• Avoid triggers, eg: caffeine
• Smoking cessation
• Selective sympathectomy
• Botox injections

Pharmacological 
- 1st line: dihydropyridine CCB (nifedipine) 
- 2nd line: 
Angiotensin II receptor antagonist
Phosphdiesterase-5 inhibitors: sildenafil 
Topical or systemic nitrates 
Alpha blockers 
SSRI 
Antiplatelet/statin therapy 
- If severe 
IV prostacyclin: iloprost

Question 12

Treatment for digital ulcers

Answer 12

• IV iloprost
• Phosphdiesterase-5 inhibitors: sildenafil
• Endothelin 1 blocker: bonsentan

Question 13

Gastrointestinal symptoms

Answer 13

• More than 70% of patients with SSc have clinical gastrointestinal involvement. Upper involvement is common, with fibrosis causing pharyngeal dysfunction, esophageal hypomotility, and lower esophageal sphincter incompetence.
• Consequences include dysphagia, chronic gastroesophageal reflux (90%), esophagitis, stricture, Barrett esophagus, and pulmonary microaspiration.

Tx: antireflux with PPI or H2 blocker

Question 14

Characteristics of scleroderma renal crisis

Answer 14

• Life-threatening rapidly progressive renal impairment usually occurring within 5 years of disease onset

Characterised by

• abrupt onset of moderate to severe HTN
• Normal urine sediment or only mild proteinuria with few cells or casts
• The most important warning sign is a sudden rise in blood pressure. Other symptoms are headache, visual disturbances, shortness of breath, chest pain or discomfort, or mental confusion.

Occurs in patients with diffuse Sc

RF: RNA polymerase III, tendon friction rubs

Triggers include corticosteroids, to reduce scleroderma renal crisis, it is recommended to use <15mg steroids especially for diffuse scleroderma

Question 15

Signs of severe scleroderma renal crisis

Answer 15

Reflects the underlying vasculopathy and marked HTN

• Microangiopathic haemolytic anaemia and thrombocytopenia
• HF and flash APO
• Blurred vision due to retinopathy
• Headache/fever/malaise
• Encephalopathy - complicated by generalised seizures
• Pericardial effusion

Question 16

Management of scleroderma renal crisis

Answer 16

ACEI - most experience with captopril (rapid onset, short duration of action)
The mechanism of action of ACE inhibitors is believed to be mitigation of the effect of interstitial fibrosis and vascular dysfunction in the glomerular arterial bed.

Evidence of CNS involvement: captopril and IV nitroprusside

Question 17

Treatment for pulmonary arterial hypertension

Answer 17

• All patients with PAH should be considered for oxygen supplementation.
• Vasodilating agents, including phosphodiesterase-5 inhibitors (sildenafil or vardenafil) and prostacyclin analogues (iloprost, epoprostenol, or treprostinil), have demonstrated efficacy in relieving symptoms of PAH associated with SSc.
• Endothelin receptor antagonists (bosentan and ambrisentan) have also shown efficacy in improving symptoms and delaying progression of PAH in SSc.
• Select patients may benefit from a vasodilator in combination with an endothelin receptor antagonist. Patients with PAH must be closely monitored using 6-minute walk tests and serial RHC studies

Question 18

Characteristics of mixed connective tissue disease

Answer 18

Overlap syndrome of SLE, scleroderma and/or polymoyositis with anti-RNP ab.
ANA very high titre in speckled pattern
Mortality increased due to pulmonary arterial hypertension

Question 19

Antibody associated with limited SsC and complication

Answer 19

Anti centromere

Pulmonary HTN

Question 20

Antibody and complications associated with diffuse SSc

Answer 20

Bad disease
Potentially extensive cutaneous, MSK and internal organ complications

• SCL70/topoisomerase I: ILD
• RNA polymerase I/III: severe renal and skin

Question 21

Pulmonary manifestations of SSc

Answer 21

> 20% extent a useful marker for progression

ILD: normally NSIP (most common)

Question 22

Cardiac manifestations of scleroderma

Answer 22

• Arrhythmias/conduction defects: ventricular Ectopics –> VT (increased in late limited SSc)
• Myocarditis (often with skeletal muscle disease
• Cardiac fibrosis
• Valvular heart disease

Question 23

MSK effects of systemic sclerosis

Answer 23

• Arthritis is not common but associated with CCP/RF and mostly reflects an overlap disease
• TENDON involvement especially common in diffuse Ssc with RNA polymerase III - friction rubs!
• Contractures
• Calcinosis

Question 24

Gastroinestinal manifestations

Answer 24

• Most frequent internal organ manifestation
• Dental disease
• Oesophageal involvement - universal
• Delayed gastric emptying
• GAVE ( Gastric antral vascular ectasia )
• Small bowel overgrowth (increased folate)
• Diverticular disease

Question 25

Scleroderma and pregnancy

Answer 25

• Limited it ok
• Increased rate of spontaneous abortion especially in severe diffuse SSc
• Increased risk of HTN, preeclampsia
• Increased risk of preterm birth and IUGR
• Consider impact of organ complications during pregnancy (PHTN is a contrandication)
• Consider medications careully - cannot use MMF, MTX, bosentan)

Question 26

Stem cell transplant in scleroderma

Answer 26

• Non smokers without PHTN or cardiac disease and extensive prior cyclophosphamide do best
• Short term increased mortality offset by longer benefit

Question 27

Mixed connective tissue disease

Answer 27

Overlap syndrome - features of SLE, scleroderma, rheumatoid, myositis

• Raynaud very common, hand oedema, arthralgia/arthritis
• Myositis, trigeminal neuralgia
• ILD
• Pulmonary HTN - commonest cause of death

“puff hands”, RNP without dsDNA = MCTD

Question 28

Mixed connective tissue disease lab

Answer 28

• ANA speckled
• U1RNP
  SSA often positive
• Leukopenia, thrombocytopenia
• High ESR
• 70% RF positive

Puff hands, RNA without dsDNA = MCTD

Question 29

Cryo and Sjogrens

Answer 29

Normally type 2

Question 30

Which of the following is associated with the highest risk of scleroderma renal crisis?
A. Presence of anti-RNA polymerase III antibodies
B. Presence of tension friction rubs
C. Treatment with ciclosporin
D. Treatment with systemic glucocorticoids

Answer 30

B. Presence of tension friction rubs
All of these options are associated with an increased risk of scleroderma renal crisis, however the presence of tendon friction rubs is often a sign of aggressive disease, and a marker of increased risk of internal organ involvement (including renal crisis).