Systemic sclerosis

Definition

Systemic sclerosis is a multisystemic disease characterised by inflammatory processes, fibrosis of the skin and internal organs and generalised vasculopathy. It is characterised by thickening and hardening of the skin (scleroderma) and secondary Raynaud's syndrome. The disease is associated with the formation of autoantibodies.

Frequency and incidence

Incidence approx. 18 people per 1 000 000 per year; women are affected 3-4 times more frequently than men. The disease usually begins between the ages of 30 and 50 and occurs worldwide, with regional variations in frequency.

Pathogenesis

The causes of the disease are unknown. Systemic sclerosis is considered to be a multifactorial disease in which individual genetic factors (gene poly-
morphisms) interact with environmental factors to contribute to the development of the disease.
The pathogenetic mechanisms that contribute to the development of systemic sclerosis are not sufficiently defined. Endothelial cells, fibroblasts, epithelial cells, cells of the immune system and their mediators contribute to the disease process. Several observations point to initial endothelial cell damage; however, the triggering factors are unknown. The damage to the endothelial cells is accompanied by increased formation and release of vasoactive substances (endothelin-1, etc.), which initiate vascular remodelling processes. Increased expression of adhesion molecules on the endothelial cell surface leads to extravasation of leukocytes. Lymphocytes accumulate in the perivascular tissue and release inflammatory mediators, which in turn contribute to disturbed vascular homeostasis and stimulate connective tissue cells to form basic substance (collagen). Fibrogenic factors (PDGF, platlet derived growth factor; CTGF, connective tissue growth factor; TGF-b, transforming growth factor-b; ET-1, endothelin-1) are increasingly detectable compared to healthy tissue.

Tissue damage in conjunction with activation of immune cells could give rise to aberrant cellular and humoral immune reactions, which are expressed in autoimmune phenomena. In many patients, autoantibodies occur primarily against nucleolar antigens. The pathogenetic significance of these autoantibodies remains unclear for the time being.

Disease pattern and progression

Systemic sclerosis is a multi-organ disease with widespread organ involvement. The extent and speed of progression are highly variable and unpredictable.

Two main manifestions

Depending on the extent of skin involvement, systemic sclerosis is categorised into diffuse cutaneous systemic sclerosis and limited cutaneous systemic sclerosis:

• diffuse cutaneous systemic sclerosis with severe skin involvement (hands, lower and upper arms, shoulder girdle, upper body, abdominal region) and often early, rapidly progressive interstitial lung disease.
• Limited cutaneous systemic sclerosis with peripheral skin involvement (hands, forearms, face) and isolated pulmonary arterial hypertension as a frequent (up to 30%) complication. This form of systemic sclerosis was referred to as CREST syndrome according to an older terminology (calcinosis, Raynaud's, oesophageal motility disorder, sclerodactyly and pronounced telangiectasia).
• angiectasia); renal involvement, on the other hand, is rare.

General symptoms

The systemic nature of the disease is characterised by fatigue, feeling cold, reduced performance, loss of appetite and weight loss.

• Skin
  Initially, a feeling of tightness and itching develops with diffuse, oedematous swelling of the hands, forearms and face with signs of hyperhidrosis. This is followed by increasing thickening of the skin with atrophy of the epidermis (loss of skin folds and sweat glands), deformation of the fingers (contractures, sclerodactyly), immobility, microstomia, shortening and sclerosis of the frenulum of the tongue and the appearance of telangiectasia. In diffuse cutaneous systemic sclerosis, the thickening of the skin also affects the trunk and is often accompanied by hyperpigmentation.
  Subcutaneous calcifications in the area of the hands (Thibièrge-Weissenbach syndrome), which are radiologically detectable, can exulcerate. The changes cause a particular vulnerability of the skin; finger ulcerations with secondary infections are a frequent complication of the disease. For a semi-quantitative assessment of skin involvement, the thickening of the skin and the fixation of the skin to underlying structures in several areas of the body are determined (modified Rodnan skin score). Not all patients with systemic sclerosis develop skin changes (systemic sclerosis sine scleroderma).
• Vasculopathy
  The most obvious manifestation of vasculopathy is Raynaud's phenomenon, which occurs in over 90% of patients and often precedes other organ manifestations for years. Triggered by cold stimuli, stress or simply a change in the outside temperature, vasoconstriction of the finger arteries occurs with typical triphasic discolouration (white, blue, red) of individual or all fingers. Vasculopathy of the finger arteries is accompanied by profound pathological changes in all layers of the arterial wall and causes a narrowing of the vessel lumen. In contrast to the more common primary Raynaud's syndrome, in which a functional disorder leads to seizure-like vasoconstriction, in systemic sclerosis structural vascular changes are associated with the seizure-like spasm of the arteries. As a result of chronic digital ischaemia, extremely painful and agonising finger ulceration and ischaemic necrosis (gangrene) can occur in conjunction with fibrotic changes to the skin (sclerodactyly). As an expression of microangiopathy, characteristic avascular fields, convoluted megacapillaries and microhaemorrhages are found in the capillary microscopy of the nail fold. The number of normal capillaries is significantly reduced.
  The generalised vasculopathy associated with systemic sclerosis not only affects the finger arteries and capillaries of the skin, but also appears as a renal crisis, pulmonary arterial hypertension or in the form of gastric vascular ectasia (see below).
   
• Pulmonary involvement
  Over 80% of patients with systemic sclerosis develop lung changes and the vast majority of patients die as a result of the lung disease. There are two main forms of lung involvement: interstitial lung disease (fibrosing alveolitis) and pulmonary arterial hypertension (PAH). These forms can occur in isolation or in combination; both are associated with reduced life expectancy (right heart failure). Patients with diffuse cutaneous systemic sclerosis often develop interstitial lung disease in the early stages of the disease. In contrast, patients with limited cutaneous systemic sclerosis have a significantly higher risk of developing isolated PAH without serious interstitial changes.
   
• Interstitial lung disease
  Due to its frequency (75% of patients with varying degrees), all patients with systemic sclerosis should be examined for interstitial lung disease. It is detected by means of pulmonary function testing and computed tomography of the thorax with high-resolution parenchymal slices (HRCT). The lung function test includes spirometry, determination of lung volumes and the diffusion capacity for carbon monoxide (DLCO). Milky glass shadows in HRCT may indicate an active inflammatory process as a sign of alveolitis; however, they are not specific, so bronchoscopy should be considered in some cases.
  If increased neutrophil and eosinophil granulocytes can be detected in the lavage fluid, this indicates florid alveolitis. The progressive destruction of the lung parenchyma initially manifests clinically as exertional dyspnoea, later as resting dyspnoea. On auscultation, fine bubbling rales can be heard, especially in the basal lung sections.
   
• Pumonal arterial hypertension (PAH)
  PAH affects around 15-30% of patients with systemic sclerosis; it occurs more frequently in limited cutaneous systemic sclerosis and is typically a late manifestation of the disease. As a consequence of the vasculopathy associated with systemic sclerosis, it is accompanied by pathological changes in the pulmonary arteries. As the symptoms of PAH are non-specific at the beginning of the disease process (exertional dyspnoea) and often only occur after a longer course of the disease, all patients with systemic sclerosis should be referred for echocardiography; this is the first step in the detection of PAH. However, Doppler echocardiography is not very reliable, so a right heart catheterisation is necessary for a definitive diagnosis.
  Invasive catheter examination is indicated in patients with symptoms of PAH (exertional dyspnea, chest pain, presyncope, syncope) and if echocardiographic PAH is suspected. In patients with SS and normal lung function, a significant decrease in diffusion capacity (DLCO < 65% or decrease > 20% within one year) may indicate the development of PAH, so these patients need to be evaluated with extra care and at shorter intervals. If PAH is detected, regular exercise tests (6-minute walk test, spiroergometry) are indicated for follow-up.
  The pulmonary manifestation of systemic sclerosis is usually the determining prognostic factor of the disease. In view of the therapeutic possibilities, a detailed initial examination and, depending on the progression and symptoms, close follow-up examinations (quarterly to half-yearly) and annual basic examinations (pulmonary function, DLCO, HRCT, echocardiography) are indicated. These examinations allow for early detection of the lung disease; allow to assess the extent of the changes, their progression and the response to therapy of the life-threatening pulmonary manifestation.
   
• Gastrointestinal tract

  Nearly 90% of patients develop disorders in the gastrointestinal tract, which may, however, be asymptomatic. Fibrosis and vasculopathy cause a degeneration of the nervous structures (Auerbach-Plexus, Meissner-Plexus). Oesophageal dysmotility, heart failure with reflux oesophagitis are the most common symptoms that cause discomfort. However, all sections of the gastrointestinal tract, from the oral cavity to the anus, may be affected.
  
  Accordingly, the symptoms are manifold: gingival bleeding (periodontitis), heartburn, difficulty swallowing, diarrhoea, constipation, flatulence, abdominal cramps (pseudoileus, ileus), mass stool (malabsorption) and stool incontinence. Oesophagitis and vascular ectasia in the stomach can cause chronic bleeding and iron deficiency. Primary biliary cirrhosis is uncommon in association with limited cutaneous systemic sclerosis, particularly in women.

• Renal involvement
  Autoptically, up to 80% indicate renal manifestation of the disease. Mild proteinuria, discretely reduced glomerular filtration rate or hypertension can be detected in approximately 50% of patients. About 10–15% of patients develop severe, life-threatening kidney disease in the sense of a renal crisis. Renal crisis is the second most common cause of death, occurring more frequently in diffuse cutaneous systemic sclerosis than limited cutaneous systemic sclerosis, and higher corticosteroid doses are considered a risk factor. It is characterised by rapidly progressive acute renal failure, usually associated with malignant hypertension (headache, visual disturbance, pulmonary oedema, hypertensive encephalopathy).
  
  Urine analysis shows only mild proteinuria. As an expression of renal vasculopathy (intima- and media hyperplasia, necrosis of the arterial wall, microthrombi), an increase in fragmentocytes (microanigiopathic haemolytic anemia) can be detected in the peripheral blood. Haemodialysis and the use of high-dose ACE inhibitors have significantly improved the prognosis of renal crisis; organ damage may be reversible, at least partially.
   
• Heart involvement
  Cardiac symptoms are associated with poor prognosis. For these patients, the 5-year survival rate is only 25%. Cardiac complications occur mainly secondary, as a consequence of arterial hypertension or PAH. Primary cardiac manifestations of systemic sclerosis include: myocardial fibrosis, myocarditis, conduction disorders, arrhythmias and pericarditis. Symptomatic pericarditis occurs in approximately 10 to 15% of patients, often associated with renal crisis.
  
  The characteristic histopathological picture of spotted myocardial fibrosis is most likely caused by recurrent vasospasm of the smaller arteries. Echocardiography shows occasional systolic, but more frequently diastolic, ventricular dysfunction. Unlike other inflammatory-rheumatic systemic diseases, there is no evidence that SS is associated with an increased risk of coronary atherosclerosis. Excitation conduction disorders and arrhythmias are common complications of systemic sclerosis; they are probably caused by fibrosizing processes in the excitation conduction system and contribute to the increased occurrence of sudden cardiac death in systemic sclerosis.
   
• Joints and Musculature
  DkSS usually manifests initially with a diffuse, edematous swelling of the hands, associated with morning stiffness, joint and muscle pain. Erosive polyarthritis (synovial inflammation) is rather uncommon. Joint pain and contractures, especially of the finger joints, result from fibrosis of the skin and periarticular structures (tendon sheaths), which clinically occasionally become audible or palpable as tendon rubbing. In conventional X-ray examination of the hands, resorptive changes on the acre (acro-osteolysis) and subcutaneous calcifications (about 40% in limited cutaneous systemic sclerosis) are often detectable. Up to 15% of patients develop myositis, with discrete proximal muscle weakness, dysphagia and mild increase in muscle enzymes.

Therapy

Up to date, no therapy has been established that would generally influence the course of the disease of systemic sclerosis. Due to the complexity of the disease, it is desirable that patients be cared for in a specialised centre. Cyclosporin A may counteract skin fibrosis, but its use is limited due to its known nephrotoxic effect. Corticosteroids do not show a lasting effect on the course of the disease, they may promote renal crisis and therefore remain reserved for specific indications (see below). Similarly, methotrexate and D-penicillamine have not been shown to have a confirmed effect. The significance of recent developments (tyrosine kinase inhibitors, B-cell depletion, anti-cytokine therapy, and more) remains to be seen. However, specific organ manifestations and complications of the disease are amenable to therapeutic intervention:

• Skin manifestation
  Diltiazem may be effective in calcinosis, colchicine was not effective in the treatment of subcutaneous calcifications. Therapeutic gymnastics to prevent contractions, paraffin hand baths to improve the mobility of the fingers.
• Secondary Raynaud syndrome
  Calcium channel blockers, prostacyclin analogues. In addition, warming gloves and heat application (hot air, hand oven) are helpful.
• Digital ulcers
• Prostacyclin analogues, bosentan for prophylaxis in recurrent ulcers, antibiotics for infections, sildenafil may assist in healing of finger ulcers.
• Florid alveolitis
  Cyclophosphamide is used for fulminant courses. High-dose cyclophosphamide therapy with autologous stem cell transplantation is considered an experimental form of therapy. At present, however, this should only be carried out in the context of study protocols. With a less aggressive course, azathioprine is considered.
• Pulmonary arterial hypertension
  The endothelin receptor antagonists (bosentan, ambrisentan) and the phosphodiesterase-5 inhibitor sildenafil are two new classes of compounds for the treatment of PAH. In severe cases, prostacyclin analogues (as long-term therapy with pump application or inhalation) are used. Diuretics for right heart failure, oral anticoagulation as an adjunctive measure.
• Renal involvement/renal crisis
  aggressive control of systemic blood pressure is the most important measure to treat renal crisis. ACE inhibitors are the therapy of choice. If this does not produce an adequate reduction in blood pressure, combination therapy with calcium channel blockers is indicated. Angiotensin receptor blockers should be reserved for patients who have a poor tolerance to ACE inhibitors; they are less effective than ACE inhibitors in this indication. In some cases, kidney replacement therapy (haemodialysis) may be necessary. However, renal function may improve after weeks and months with adequate therapy.
• Arthralgia/ Arthritis
  symptomatic therapy with acetaminophen, NSAIDs in combination with proton pump inhibitors or low-dose glucocorticoids. Caution should be exercised when prescribing glucocorticoids as they increase the risk of developing renal crisis.
• Myositis
  Glucocorticoids in adequate but lowest possible doses as monotherapy or in combination with methotrexate or azathioprine.
• Pericarditis
  NSAIDs, if not enough glucocorticoids. Surgical intervention if necessary.
• Oesophageal dysmotility/ reflux oesophagitis
  Proton pump inhibitors in symptomatic reflux oesophagitis and for the prevention of oesophageal strictures. Prokinetics such as erythromycin may be helpful in symptomatic oesophageal dysmotility.
• Sicca syndrome
  artificial tear fluid or artificial saliva. Humidifier as a supportive measure. Comprehensive dental hygiene for caries prophylaxis.

Forecast

The 10-year survival rate after initial diagnosis is approximately 70–80%. Men have a poorer prognosis; manifestations in the heart, lungs and kidneys are associated with higher mortality.

Fact box

Systemic sclerosis is a rheumatic systemic disease involving multiple organs (fibrosis, vasculopathy, inflammation). The course of the disease is variable, the prognosis is determined by the organ manifestations.

Organ manifestations

• Skin
  Sclerodactylia, sclerosis of the skin of the face (microstomy, perioral radial furrows), lower and upper arms, shoulder girdle and chest, shortening and sclerosis of the tongue band, facial telangiectasia, hyperpigmentation, subcutaneous calcification of the hands (Thibièrge-Weissenbach syndrome), finger ulceration with secondary infections and sec. Raynaud syndrome
• Lung
  Alveolitis, pulmonary fibrosis, pulmonary arterial hypertension
• Heart
  Myocardial fibrosis, arrhythmias, pericarditis
• Kidney
  renal crisis, arterial hypertension
• Gastrointestinal tract
  Frenulum linguae thickening, oesophageal dysmotility, cardiac insufficiency with reflux oesophagitis gastric vascular ectasia, malabsorption, subileus, ileus
• Musculoskeletal system
  Myositis, Arthritis (rare), Joint contractures

The prognosis of systemic sclerosis is crucially determined by lung involvement. Regular, yearly examinations for the detection of lung disease such as HR-CT, lung function testing including determination of diffusion capacity (DLCO) are essential. For pulmonary arterial hypertension, echocardiography should be performed annually. Regular monitoring of blood pressure is indicated in order to detect renal involvement (renal crisis) as early as possible.

Due to the complex course of the disease and the multi-organ attack with potentially life-threatening manifestations, it is desirable that patients be cared for in a specialised centre.

Dr. H.P. Kiener, Dr. P. Petera, Univ. Prof. J.S. Smolen