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RitvaPeltomaa

Systemic Sclerosis

Essentials

Systemic sclerosis is characterized by small vessel injuries, immunological abnormalities, and induration and shrinking of connective tissue.
Scleroderma refers to the skin manifestations of systemic sclerosis. Systemic sclerosis and scleroderma are often used as synonyms.
Systemic sclerosis is classified into a diffuse (generalized) and a limited form. In addition, there is an overlap syndrome with features of both systemic sclerosis and another systemic rheumatic disease.

Epidemiology

The prevalence of systemic sclerosis is 38-341 cases per one million people.
The incidence is highest in women aged 30-50 years.

Symptoms

Raynaud's phenomenon (pictures 1 2)Raynaud's Phenomenon (Rp) or White Finger Disease can be observed in almost every patient with systemic sclerosis..
- In the limited form of the disease, it may precede the other symptoms by as long as several decades.
- The condition may lead to ulcerations and scars on the fingertips and toes (picture 3).
- Ulcers on fingers may take as long as 3 months to heal.
Skin changes occur, especially in the face, hands and feet.
- First there is swelling of the skin (picture 4), then thickening and gradually atrophy (pictures 5 6).
- In the limited form of the disease the skin lesions occur in the face and on the extremities distal to the knees and elbows.
- In diffuse systemic sclerosis the skin symptoms are more widespread.
Most patients (80-90%, in both subclasses) have telangiectasia.
20-30% of all patients have arthralgia and myalgia.
There are symptoms from the gastrointestinal tract.
- Particularly dysphagia, reflux oesophagitis and oesophageal strictures.
- Malabsorption
- Constipation and faecal incontinence may be present in as many as one patient in two.
Lung fibrosis, pulmonary hypertension Increased Pulmonary Blood Pressure: Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension
Pericarditis Pericarditis, heart failure Chronic Heart Failure, arrhythmia
Proteinuria Proteinuria, impaired renal function Increased Blood Creatinine Concentration, Egfr and Renal Function Tests and elevated blood pressure are not uncommon.
- The most severe renal complication is the scleroderma renal crisis characterized by highly elevated blood pressure, rapidly progressing renal failure and microangiopathic haemolytic anaemia.

Types of systemic sclerosis

Type of disease	Typical features
Limited systemic sclerosis (previously called the CREST* syndrome)	Skin lesions distal to the knees and elbows Raynaud's phenomenon occurring a long time before the other symptoms Commonly late complications Commonly elevated pulmonary arterial pressure and severe bowel disease Centromere antibodies
Diffuse (generalized) systemic sclerosis	Skin lesions more proximally and also on the trunk Raynaud's phenomenon either concomitantly with or slightly before the other symptoms Increased risk of renal lesions, and heart symptoms Severe interstitial lung disease (ILD) Type I topoisomerase (Scl-70) antibodies, RNA polymerase III antibodies
Systemic sclerosis in the absence of scleroderma	No thickening of the skin Raynaud's phenomenon Internal organ lesions or circulatory changes Typical serological findings associated with systemic sclerosis or capillaroscopic changes consistent with systemic sclerosis

*CREST: C = calcinosis, R = Raynaud's phenomenon, E = (o)esophageal motility disorder, S = sclerodactyly, T = telangiectasia
Modified from: Peltomaa R. [Systemic sclerosis, its incidence, prevalence and etiopathogenesis], table 1. In: Kauppi M, Karjalainen A, Pirilä L, et al. (Eds.). [Rheumatic diseases]. Duodecim Publishing Company Ltd, 2023.

Investigations and diagnosis

When suspecting systemic sclerosis, the following investigations are recommended in primary health care: ESR, CRP, basic blood count with platelet count, antinuclear antibodies, creatinine, chemical urinalysis.
The following combination is regarded as a "red flag", which should lead to suspecting early systemic sclerosis and a consultation in specialized health care
- Raynaud's phenomenon
- swollen fingers and
- a positive result in antinuclear antibody test.
The diagnosis of systemic sclerosis is confirmed within specialized care.
The most important further investigations
- Determination of specific autoantibodies
  - Anticentromere antibodies
  - Type I topoisomerase, i.e. Scl-70 antibodies
  - RNA polymerase III antibodies
- Videocapillaroscopy
- Skin biopsy, as necessary
In systemic sclerosis
- ESR is often moderately increased.
- CRP is normal or slightly elevated.
- Basic blood count is usually normal; leucopenia and thrombocytopenia occur clearly less frequently than in SLE.
- Antinuclear antibodies are found in about 90%.
- Nucleolar staining pattern is typically either centromere or nucleolar.
Centromere antibodies are found in those with the limited disease form.
- This disease form is associated with an increased risk of elevated pulmonary artery pressure.
Type I topoisomerase antibodies are usually associated with the diffuse form of the disease and an increased risk of pulmonary fibrosis.
RNA polymerase III antibodies are usually associated with the diffuse form of the disease, rapidly progressive thickening of the skin and renal crisis.
Videocapillaroscopy is an important method in distinguishing between primary and secondary Raynaud's phenomenon (picture article 7).
- Changes in the nailfold capillaries are found in over 80% of patients with systemic sclerosis, and the abnormalities correlate with the severity of the disease.
A chest radiograph helps to assess the pulmonary status. High-resolution computed tomography and pulmonary function tests must always be done in early disease.
Subcutaneous calcifications and acrolysis in the fingers, both typical for the disease, may be found in radiographs of the hands and feet.
With respect to the gastrointestinal system, the most important investigation is oesophagogastroduodenoscopy.

Treatment Calcium-Channel Blockers for Raynaud's Phenomenon in Systemic Sclerosis, Iloprost and Cisaprost for Raynaud's Phenomenon in Progressive Systemic Sclerosis, Methotrexate in the Treatment of Systemic Sclerosis, Proton Pump Inhibitors, H2-Receptor Antagonists and Prokinetics for Gastro-Oesophageal Reflux, Cyclophosphamide for Connective Tissue Disease-Associated Interstitial Lung Disease, Angiotensin Converting Enzyme Inhibitors in Treatment of Scleroderma Renal Crisis, Endothelin Receptor Antagonists for Pulmonary Arterial Hypertension, Phosphodiesterase 5 Inhibitors for Pulmonary Hypertension, Inhaled Iloprost for Pulmonary Hypertension, Interventions for Morphea, Phosphodiesterase 5 Inhibitors for Raynaud's Phenomenon

The patient should protect his or her skin, avoid cold and stop smoking.
Calcium channel blockers are first-line drugs for peripheral circulatory disturbances. Angiotensin receptor blockers (ARBs), phosphodiesterase-5 inhibitors or selective serotonin reuptake inhibitors (SSRIs) may also be tried.
Intravenous prostacyclin analogues can be used for severe vasculopathy of the fingers or toes.
The endothelin receptor antagonist bosentan and phosphodiesterase-5 inhibitors have proved useful in preventing recurrence of finger ulcerations.
Methotrexate may be considered for the treatment of cutaneous changes in early diffuse systemic sclerosis. Despite lack of scientific evidence, methotrexate is also used for the limited type of the disease. Rituximab or tosilizumab can also be used in severe cases.
Non-steroidal anti-inflammatory drugs are the first choice for arthralgia and myalgia.
Glucocorticoids, as well as methotrexate if needed, are prescribed for arthritis and myositis. Biological therapy (most commonly rituximab or tosilizumab) may also be considered in the treatment of the most severe cases of arthritis.
- Blood pressure and renal function should be regularly monitored in patients taking glucocorticoids.
Proton pump inhibitors are used for gastro-oesophageal reflux symptoms.
Mycophenolate or tosilizumab can be used in the inflammatory phase of the pulmonary disease. Cyclophosphamide or rituximab can also be used in more severe cases. In the fibrotic phase, nintedanib can be used alone or combined with mycophenolate.
Angiotensin converting-enzyme inhibitors are the first choice for the treatment of hypertension and renal crisis.
Endothelin receptor blockers, phosphodiesterase inhibitors and prostacyclin analogues can be used for the treatment of pulmonary hypertension Increased Pulmonary Blood Pressure: Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension.

Systemic sclerosis and pregnancy

Risk of prematurity and low birth weight
Pregnancy planning is important.
In active disease, pregnancy is almost contraindicated.

Prognosis

The prognosis is favourable when the disease is confined to the skin
Signs of unfavourable prognosis
- Young age at the onset of disease
- Male sex
- African descent
- Diffuse disease
- Type I topoisomerase antibodies
- Cardiac and renal changes
- Interstitial lung disease
- Elevated pulmonary arterial pressure
- Malignancies

References

Kauppi M, Karjalainen A, Pirilä L, et al. (Eds.). [Rheumatic diseases]. Duodecim Publishing Company Ltd, 2023.
Pope JE, Denton CP, Johnson SR, et al. State-of-the-art evidence in the treatment of systemic sclerosis. Nat Rev Rheumatol 2023;19(4):212-226 [PubMed]
Hachulla E. EULAR Textbook on Systemic Sclerosis. 2nd edition, 2019.
Denton CP, Khanna D. Systemic sclerosis. Lancet 2017;390(10103):1685-1699 [PubMed]
Kowal-Bielecka O, Fransen J, Avouac J, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis 2017;76(8):1327-1339 [PubMed]
van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis 2013;72(11):1747-55 [PubMed]

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