Scleroderma Flashcards
What is scleroderma?
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.
Subtypes
Limited cutaneous systemic sclerosis (lcSSc)
Diffuse cutaneous systemic sclerosis (dcSSc)
Systemic sclerosis without scleroderma
Limited cutaneous systemic sclerosis (lcSSc):
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)
Diffuse cutaneous systemic sclerosis (dcSSc):
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.
Systemic sclerosis without scleroderma:
presence of typical systemic features and serological markers of SSc in the absence of skin lesions.
Epidemiology
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.
Aetiology
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.
Predominant organs involved
Skin
Lungs
Heart
Gastrointestinal tract
Kidneys
Musculoskeletal system
Nervous system
Vascular changes
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.
What does vascular damage lead to?
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.
What do these growth factors cause?
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.
Autoantibodies
estimated 95% of patients with SSc have autoantibodies to nuclear antigens. ANAs
Anti-nuclear antibodies
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.
Extractable nuclear antigens
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.
What are the extractable nuclear antigens
Anti-Scl-70
Anti-centromere
Anti-RNA polymerase III
Anti-PM-Scl
Anti-U1 RNP
Classic changes
- Pruritus
- Loss of hair
- Dryness
- Puffy appearance due to oedema
- Ulcerations
What is found in scleroderma
Raynaud phenomenon - refers to skin colour changes that occur in the fingers and toes from vasospasm
CREST syndrome
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.
Mnemonic for CREST
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
Systemic manifestations
Pulmonary hypertension
Pericardial disease
Interstitial lung disease
Oesophageal dysmotility
Arthritis
ED
What is scleroderma renal crisis
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.
What is scleroderma renal crisis characterised by?
Sudden onset severe hypertension
Acute kidney injury
Relatively bland urinalysis
What is scleroderma renal crisis considered as
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).
Treatment for scleroderma renal crisis
use of angiotensin-converting enzyme (ACE) inhibitors.
Without treatment, ESRD may develop within 1-2 months with high one-year mortality.
Diagnostic factoes
- 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
Investigations
Urinalysis
FBC
ESR CRP
Echocardiogram
Trearment for limited
manage vascular complications
Treatment for diffuse
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).
Overlap syndrome treatment
management should focus on the severity and activity of the overlap conditions (e.g. arthritis, SLE, myositis).
Organ based complications treatmetn
- 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
Prognosis
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.
