18th January 2024

Emergencies in Systemic Sclerosis

Background

Systemic sclerosis – also known as Scleroderma – is an autoimmune multi-system connective tissue disease characterised by increased fibroblast activity causing abnormal growth and deposition of collagen, vascular damage and fibrosis of connective tissues. This usually occurs in the skin (hence the name scleroderma) along with internal organs such as the GI tract, lungs and heart. It can also occur in the vasculature, resulting in manifestations such as Raynaud’s, pulmonary arterial hypertension and renal disease. Typical cutaneous features of systemic sclerosis include microstomia and ‘salt-and-pepper’ appearance of skin due to areas of hypo- and hyper-pigmentation.

Classification of systemic sclerosis

Systemic sclerosis has two main subtypes:

1. Limited cutaneous systemic sclerosis (more common type)
   • The areas of skin involved include the face, arms (distal to the elbows) and legs (distal to the knees)
   • Additional features can be summarised as CREST (CREST syndrome is the old name for this sub-type): Calcinosis, Raynaud’s, oEsophageal dysmotility, Sclerodactyly, Telangiectasia
   • Slow onset and progression
2. Diffuse cutaneous systemic sclerosis (less common type)
   • The areas of skin involved include the trunk, proximal arms to the elbow and proximal legs to the knee
   • Higher mortality due to higher incidence of multi-organ involvement 
   • Rapid onset with early skin thickening and Raynaud’s

Antibodies

There are a number of antibodies associated with systemic sclerosis, and each has associations with particular complications which can help with screening and prognostication.

• Anti-topoisomerase-1 antibody (also known as anti-Scl-70): strong association with lung fibrosis, renal disease, and poor prognosis.
• Anti-centromere antibody (ACA): seen in patients with limited cutaneous systemic sclerosis; associated with pulmonary hypertension.
• Anti-RNA-polymerase-III antibody: seen in patients with diffuse cutaneous systemic sclerosis and strongly associated with renal disease, and in particular, ‘scleroderma renal crisis’.

Scleroderma Renal Crisis

Scleroderma renal crisis is a life-threatening complication, presenting with sudden-onset malignant hypertension and severe progressive renal failure. Other manifestations include hypertensive encephalopathy, congestive cardiac failure and microangiopathic haemolytic anaemia.

It most commonly presents in patients with the diffuse cutaneous sub-type; it is very rare in those with limited cutaneous disease. It usually occurs early in the disease course and can occasionally be the presenting feature.

Pathophysiology

Blood vessels undergo structural changes (thickening and proliferation of the intima with fibrin deposition), which causes reduced blood flow, further exacerbated by vasospasm. When this occurs in the kidneys, renal ischaemia develops, causing activation of the renin-angiotensin-aldosterone system (RAAS) and subsequent rise in blood pressure. The hypertension causes even further damage to renal blood vessels, and this cycle of events eventually results in malignant hypertension and fulminant renal failure.

Management

Since activation of the RAAS is the basis of the pathogenesis of the scleroderma renal crisis, management is based on inhibition of this pathway using Angiotensin-Converting Enzyme (ACE) inhibitors. Patients should be admitted for blood pressure control and careful monitoring of renal function. Despite the potential to further worsen the renal function, ACE inhibitors are an essential part of the treatment of scleroderma renal crises. In some cases, dialysis may be needed, but renal recovery can occur up to 24 months after the crisis and decisions about transplantation should be delayed until this point.

Scleroderma Pulmonary Hypertensive Crisis

Pulmonary arterial hypertension (PAH) in systemic sclerosis is a rare but potentially fatal complication. It may occur either as a primary process or secondary to pulmonary fibrosis. Early clinical symptoms of PAH are non-specific, including breathlessness, light-headedness, syncope, fatigue and weakness. Patients should be screened at the time of diagnosis and annually thereafter. However, some patients may go unscreened, particularly if they develop a compensatory sedentary lifestyle which limits symptoms. In these patients, PAH may progress for some time and become quite severe before it is detected.

The gold standard diagnostic tool is right heart catheterisation. Patients can sometimes present acutely, and, in this case, it will be diagnosed on an echo doppler of the heart.

Clinical signs associated with PAH

• Split heart sounds with a loud P₂
• Tricuspid regurgitation (systolic murmur)
• Parasternal heave
• Raised JVP
• Ascites
• Hepatomegaly with a pulsatile liver
• Peripheral oedema

Pathophysiology

In primary pulmonary arterial hypertension, vasospasm and intimal proliferation with fibrin deposition in the lungs lead to vascular resistance and remodelling, which ultimately results in right ventricular dysfunction.

Management

Management revolves around targeting these pathways to restore the balance between vasoconstriction and vasodilation. Thus, vasodilators (nitric oxide and prostacyclin) and proliferative mediators (endothelin-1) are targeted using the following medications:

• Prostacyclin analogues, e.g. Epoprostenol, Iloprost
• Endothelin-receptor antagonists, e.g. Bosentan
• Phosphodiesterase Type-5 Inhibitors (which increase nitric oxide production), e.g. Sildenafil

In the acute setting, patients can present significantly hypoxic and, require IV prostacyclin, and may require advanced respiratory support for oxygenation. Respiratory involvement in systemic sclerosis, either pulmonary fibrosis or PAH, is the most common cause of death for patients living with this condition.

References

• Tidy C. Systemic sclerosis (scleroderma) [Internet]. Patient.info. 2022 [cited 2023 Feb14]. Available from: https://patient.info/doctor/systemic-sclerosis-scleroderma
• Vaidya PN, Basyal B, Finnigan NA. Scleroderma And Renal Crisis [Internet]. PubMed. Treasure Island (FL): StatPearls Publishing; 2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482424/
• Kolton Schneider L, Ali Y, Agnew JD. Scleroderma-Associated Pulmonary Arterial Hypertension: Early Detection For Better Outcomes [Internet]. PubMed. Treasure Island (FL): StatPearls Publishing; 2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK576387/