Scleroderma

Question 1

What is scleroderma?

Answer 1

Systemic sclerosis is a chronic, multi-system disorder that is characterised by widespread vascular dysfunction and fibrosis.

hallmark features of SSc is thickened, hardened skin known as scleroderma. The term scleroderma is often used synonymously with SSc.

Question 2

Subtypes

Answer 2

Limited cutaneous systemic sclerosis (lcSSc)
Diffuse cutaneous systemic sclerosis (dcSSc)
Systemic sclerosis without scleroderma

Question 3

Limited cutaneous systemic sclerosis (lcSSc):

Answer 3

characterised by sclerosis (hardening) of the skin in the distal limbs.

Some involvement of face and neck seen. May develop systemic features (e.g. oesophageal dysmotility, pulmonary hypertension).

May manifest the CREST syndrome (see below)

Question 4

Diffuse cutaneous systemic sclerosis (dcSSc):

Answer 4

Characterised by extensive sclerosis of the skin. May be difficult to distinguish from limited form, but considered diffuse if proximal limbs and/or trunk involvement. More likely to have rapid disease progression and internal organ involvement.

Question 5

Systemic sclerosis without scleroderma:

Answer 5

presence of typical systemic features and serological markers of SSc in the absence of skin lesions.

Question 6

Epidemiology

Answer 6

idence and prevalence of SSc varies by geographical regions and different populations. In the UK, the prevalence has previously been reported as 88-443 per million people.

SSc has a female predominance (estimated 3-6:1 female to male ratio). However, women tend to present at a younger age with lcSSc, whereas men tend to present with dcSSc and more severe systemic disease (e.g. interstitial lung disease). The majority of patients develop SSc between 20-60 years old.

Question 7

Aetiology

Answer 7

Characterised by immune-mediated damage to vascular structures (e.g. blood vessels) and excessive synthesis and deposition of extracellular matrix structures (e.g collagen). This leads to chronic fibrosis, scarring and damage to organs.

Question 8

Predominant organs involved

Answer 8

Skin
Lungs
Heart
Gastrointestinal tract
Kidneys
Musculoskeletal system
Nervous system

Question 9

Vascular changes

Answer 9

vascular changes are observed in SSc with alteration to chemical mediators involved in vascular tone (i.e. resistance to flow).

These mediators include Endothelins and nitric oxide (NO). Endothelin-1 is a potent vasoconstrictor and fibrogenic with elevated levels identified in SSc.

NO is a vasodilator and opposes the action of Endothelins. The balance between NO and Endothelin is thought to be disrupted in SSc.

Question 10

What does vascular damage lead to?

Answer 10

activation of endothelial cells, release of adhesion molecules and increased leucocyte migration into peripheral tissue. This leads to release of profibrotic cytokines, including TGF- beta, IL-4 and platelet-derived growth factor among others.

Question 11

What do these growth factors cause?

Answer 11

activate fibroblasts and lead to collagen deposition and fibrosis. This immune activation and release of profibrotic cytokines is central to the pathogenesis of SSc and why immune-mediated therapies are utilised.

Question 12

Autoantibodies

Answer 12

estimated 95% of patients with SSc have autoantibodies to nuclear antigens. ANAs

Question 13

Anti-nuclear antibodies

Answer 13

Testing for anti-nuclear antibodies (ANA) screens for the presence of antibodies that are reacting to nuclear antigens. Up to 95% of patients with SSc have a positive ANA. There are different staining patterns of ANA (e.g. diffuse, speckled, nucleolar) that depend on the ENA present.

Question 14

Extractable nuclear antigens

Answer 14

extractable nuclear antigens (ENA) refer to the specific nuclear antigen ANA antibodies are reacting to. ENA panels are usually added by the laboratory following a positive ANA. The expression of ENA is variable depending on the subtype of SSc.

Question 15

What are the extractable nuclear antigens

Answer 15

Anti-Scl-70
Anti-centromere
Anti-RNA polymerase III
Anti-PM-Scl
Anti-U1 RNP

Question 16

Classic changes

Answer 16

• Pruritus
• Loss of hair
• Dryness
• Puffy appearance due to oedema
• Ulcerations

Question 17

What is found in scleroderma

Answer 17

Raynaud phenomenon - refers to skin colour changes that occur in the fingers and toes from vasospasm

Question 18

CREST syndrome

Answer 18

CREST refers to a mnemonic for the clinical manifestations of lcSSc. The term is often used synonymously with limited SSc. The condition is associated with anti-centromere autoantibodies.

Question 19

Mnemonic for CREST

Answer 19

C - calcinosis: calcium deposits in the skin
R - Raynaud phenomenon
E - oEsophageal dysmotility: swallowing difficulty
S - sclerodactyly: skin thickening and hardening affecting the fingers and toes
T - telangiectasia: dilated capillaries. Usually appear on face, palms and mucous membranes

Question 20

Systemic manifestations

Answer 20

Pulmonary hypertension
Pericardial disease
Interstitial lung disease
Oesophageal dysmotility
Arthritis
ED

Question 21

What is scleroderma renal crisis

Answer 21

form of intrarenal arterial stenosis due to narrowing and obliteration of the vascular lumen. It is associated with the presence of the autoantibody Anti-RNA polymerase III.

Question 22

What is scleroderma renal crisis characterised by?

Answer 22

Sudden onset severe hypertension
Acute kidney injury
Relatively bland urinalysis

Question 23

What is scleroderma renal crisis considered as

Answer 23

Thrombotic microangiopathy, which refers to the occlusion of small vessels.

may be accompanied by haemolytic anaemia and thrombocytopaenia.

Other thrombotic microangiopathies include thrombotic thrombocytopaenic purpura (TTP) and haemolytic uraemic syndrome (HUS).

Question 24

Treatment for scleroderma renal crisis

Answer 24

use of angiotensin-converting enzyme (ACE) inhibitors.

Without treatment, ESRD may develop within 1-2 months with high one-year mortality.

Question 25

Diagnostic factoes

Answer 25

• Raynaud phenomenon
• Digital changes: ulceration, calcinosis, ‘salt and pepper’ skin
• Telangiectasia
• Heartburn and/or dysphagia
• Acute onset hypertension and renal impairment
• Restrictive lung disease
• Serological evidence of autoimmune disease

Question 26

Investigations

Answer 26

Urinalysis
FBC
ESR CRP
Echocardiogram

Question 27

Trearment for limited

Answer 27

manage vascular complications

Question 28

Treatment for diffuse

Answer 28

manage vascular complications and consider systemic immunosuppression. Options include Methotrexate (Dihydrofolate reductase inhibitor), Mycophenolate (Purine synthesis inhibitor), Cyclophosphamide (alkylating chemotherapy agent that crosslinks DNA and RNA) and oral corticosteroids (for severe skin disease). Autologous stem cell transplant may be used in selected cases (highly specialist therapy).

Question 29

Overlap syndrome treatment

Answer 29

management should focus on the severity and activity of the overlap conditions (e.g. arthritis, SLE, myositis).

Question 30

Organ based complications treatmetn

Answer 30

• Raynaud phenomenon: calcium channel blockers and angiotensin II receptor antagonists can be used first line.
• Severe digital ulceration: Phosphodiesterase type 5 inhibitors, endothelin receptor antagonists or intravenous prostaglandins can be used. In severe refractory cases, digital sympathectomy may be needed.
• Interstitial lung disease: depends on the extent of disease but cyclophosphamide and mycophenolate may be used
• Gastro-oesophageal reflux: proton-pump inhibitors
  Dysphagia secondary to dysmotility: prokinetics (e.g. dopamine antagonists - metoclopramide/domperidone).
• Bacterial overgrowth: intermittent broad-spectrum antibiotics
  Scleroderma renal crisis: ACE inhibitors

Question 31

Prognosis

Answer 31

risk of mortality in SSc is almost four-fold higher compared to age and sex-matched controls. The increased mortality is predominantly related to pulmonary fibrosis, pulmonary hypertension and/or cardiac disease.