Systemic sclerosis is a generalized disorder of connective tissue, leading to progressive tissue fibrosis. The condition characterized by fibrosis of the skin, but with involvement also of joints, tendons, muscles, and internal organs

The condition was first described by Curzio in the 1753. Initially it was seen as a condition affecting the Skin but in 1945, Goetz proposed a description of progressive systemic sclerosis. He described visceral lesions in autopsy cases, whilst studying Medicine and forensic pathology at the University of Cape Town, South Africa. In addition, a limited Scleroderma was described in 1964 by Winterbauer. He referred to a syndrome with calcinosis, raynauds phenomenon, esophageal dysmotility, sclerodactyly, and Telangiectasia. This subsequently became known as the CREST syndrome.

Epidemiologically, the condition is relatively rare affecting approximately 15 people per hundred thousand of the population. Very low association with geography and no clear association with genetic. The onset is in the fourth decade.
Possible associated causes have been considered. The condition has been described in South African gold miners, where it is thought to be related to silica dust exposure. It has also been found in jewelry workers and miners who worked with quartz. Some implications that chemicals such as Trichloroethylene, resins of epoxy vinyl chloride, have been described. In addition they have been some descriptions of people who live near airports having a higher incidence of Scleroderma.
Genetic association is not proven to play a large role.

A more complex explanation is that an unknown immune event causes damage to the lining of the blood vessel endothelium. This results in adherence of platelets, release of cytokines and fibroblast proliferation, and increased synthesis of the connective tissue matrix. The fibroblasts themselves produce cytokines, similar to the platelets themselves, in what becomes a vicious cycle. In addition, immune cells -- the B and T lymphocytes release Antibodies and cytokines respectively. The cytokines include transforming growth Factor Beta, and interleukin 2.

Classification of Systemic Sclerosis.
Clinically - the conditions may be divided into different sub-types.

1- Diffuse Scleroderma -- Skin thickening on the trunk face and proximal and distal extremities

2-Limited Scleroderma -- Skin thickening to sites distal to the elbow and knee but also involving face and Neck.

This includes CREST SYNDROME ( Calcinosis, Raynauds Phenomenon, Esophageal Dysmotility, Sclerodactyly, and Telangiectasia.)

3-Scleroderma sans Scleroderma -- internal organ changes and Vascular and serological features, but no skin thickening.

4- Overlap Syndrome - Criteria fulfilling Systemic Sclerosis, but including criteria for the diagnosis of systemic lupus erythematosus, Rheumatoid Arthritis or inflammatory muscle disease, such as dermatomyositis.

5- Undifferentiated connective tissue Syndrome -- Raynauds phenomena with the laboratory features of Systemic Sclerosis or clinical features of Systemic Sclerosis. The antibody features include Anticentromere Antibody and clinical features include abnormal nailfold capillaries.

The clinical features Of Scleroderma

The main clinical features center on the cutaneous manifestations, but the outcome depends on internal organ involvement.

The skin in Scleroderma.
There is a to increase in the thickening and tightening of Skin evolving through several stages. Initially there is swelling and oedema of the Skin with swelling of the Hands and fingers. Frequently, the initial complaint is of symptoms of morning stiffness, and pain in the joints of the hands. Carpal tunnel Syndrome may also be seen as an initial event. There is deposition of Glycosaminoglycan in the dermis. However local inflammation and vascular events are the main cause. There is a mild increase in the inflammatory cell population, and with platelet and other inflammatory cell response. There is an accumulation extra-cellular tissue, including collagen, Glycosaminoglycan, fibronectin, and tissue matrix. Skin thickening then begins usually in the Hands and fingers and the Skin becomes tighter. The Skin of the face and Neck then becomes involved and the lips become parsed. Mouth opening becomes limited. With the progression Skin pigment becomes increased and decreased in a patchy distribution. This is called poikiloderma.

Involvement of the Skin proximal to the metacarpophalangeal joints provides the major classification criteria for systemic sclerosis. Minor criteria, for which two are required, include sclerodactyly, the digital scarring of the fingertips, and loss of the digital palps, and pulmonary fibrosis or scarring.

The patterns of distribution of skin thickening identify the Limited type of Scleroderma versus Diffuse Scleroderma.

In the clinical setting, a diagnosis is made, and a distinction is made of the type of  disease - either diffuse or limited.
Secondly an attempt is made to chart the severity of the disease. This is done using skin scores. Using a scale --
0 equals normal,
1 equals mild,
2 equals moderate,
3 equals severe, and
4 equals extreme
Various anatomical regions are scored. These include the hands, the fingers, the forearms, the arms, the chest wall, the abdomen, the abdomen, the face, the thighs, the legs, and the feet. 

Raynauds phenomenon in Scleroderma
This is an almost inevitable finding in the majority of these patients. It is characterized by cyclical colour changes on exposure to cold and even emotional stress. It may be associated with numbness and pain of the Hands. Raynauds phenomena may occur in 20 percent of all normal patients. However in systemic sclerosis 75 percent of patients present with Raynauds phenomenon. An additional 20 percent develop Raynauds subsequently, and the 5 percent who do not develop Raynauds phenomena frequently have cardiac and the renal involvement as well, and if male, frequently tend to have a worse prognosis. The pathology seen in Raynauds phenomenon, in Scleroderma patients, is due to endothelial injury, and secondary platelet activation with adherence to the endothelium and release of vasoconstrictor factors, such as five hydroxytryptamine, thromboxane A2, and adenosine phosphate. Injured endothelium releases constrictor substances and the healthy and normal responses to these effects -- Prostacycline, monoamine oxidase, and endothelial-derived relaxation Factor, are inadequate to counter the constrictor response. The result is vascular spasm and ischemia of the periphery.
In systemic sclerosis that is a > 75 percent reduction of the arterial lumen. There is intimal hyperplasia, increased collagen deposition. Presence of blood vessel constriction, because of an increased peripheral response to cold, aggravate this problem, and it occludes the vessel completely. The vascular changes are also seen in other visceral vessels including the kidney, the heart, and the pulmonary vessels. Interestingly, it has been observed, that the peripheral exposure to cold with Raynauds phenomena, is associated with constriction of internal blood vessels, including the coronary arteries. This can be demonstrated with thallium scans.

The consequences of skin involvement are a decrease in function because of tethering of the skin.

Systemic manifestations of Scleroderma

Diffuse Scleroderma usually results in a more rapid progression of internal organ involvement compared to limited Scleroderma.
Limited Scleroderma is usually slow in progression and internal organ involvement is usually more delayed.

General symptoms :
Weight loss and generalized fatigue are extremely common. Pyrexia however is not a feature of the disease.

Gastro intestinal manifestations :
These are extremely common in Scleroderma.
Esophageal involvement occurs in all types of Scleroderma -- both diffuse and limited varieties. The main problem is a dysmotility Syndrome and is associated with incompetence of the lower esophageal sphincter, as the result of reflux of gastric contents from the stomach into the esophagus. Patients, complain of chest pain, or dysphagia -inability to swallow. Pathologic examination of the tissue of the esophagus shows atrophy of the muscle and fibrosis of the muscle and sub mucosal layers. Erosion's and perforation and of the esophagus in particular may occur. Esophageal dysmotility is also seen in primary Raynauds in the absence of Scleroderma.
Complications of esophageal involvement include ulceration, strictures, and bleeding. As a consequence of the reflux, aspiration, and aspiration pneumonia may occur, and are characterized by a morning cough or cough when lying flat.

Stomach involvement may occur, as well as small intestine and large intestine abnormalities. This is characterized again by dysmotility. Symptoms may include bloating, cramps, diarrhea, and malabsorption. Bacterial over-growth because of stasis, may occur and pseudo-obstruction may occur. Perforation may occur. Colon involvement may result in constipation and pseudo obstruction. Characteristically, on x-ray, features of pseudo-obstruction may be seen with dilated loops of bowel, as well as large diverticulae.

Pulmonary involvement :
Lung involvement is frequent, and is a cause of significant mortality and morbidity in patients with Scleroderma.
A progressive inflammation and fibrosis with obliteration of the vessels and raised pulmonary artery pressures is noted.
Clinically, patients develop progressive shortness of breath, as well as cough, chest pain, and develop crackles on auscultatory examination. Findings subsequently develop, of pulmonary hypertension with elevated venous pressures. Patients with limited Scleroderma tend to develop progressive elevation of pulmonary artery pressures despite limited pulmonary fibrosis. Chest X-ray shows increased interstitial markings. A useful investigation early on, is high-resolution CT Scan. This may show interstitial changes. The pulmonary interstitial involvement is a progressive problem, and lung functions show progressive restriction.

Cardiac involvement :
Fibrosis of the cardiac tissue occurs and if severe may results in cardiac failure with breathlessness, palpitations, and arrhythmia’s. Because of involvement of the conducting tissue, various degrees of heart block may occur. However, supra ventricular and ventricular tachycardia may also be seen. The latter are most frequently related to mortality and sudden death.

Musculoskeletal involvement :
Arthralgia and morning stiffness are seen in the majority of patients, but frank arthritis with synovitis is uncommon.
Erosions may be seen on X-Rays in approximately 10-20 percent of patients.
Tendonitis is more frequent with fibrosis of the tendon sheaths, give rise to characteristic tendon friction rubs.
Varying degrees of muscle inflammation, with features of myositis and frequently elevation of the Creatinine phosphate kinase may occur. The inflammation within the muscle is less then that seen in primary polymyositis or dermatomyositis, and is more associated with scarring and fibrosis.

X-ray changes show features of erosions of the distal phalanges, and calcinosis-calcification in sub cutaneous tissues of the fingers, and at the Elbows.

Renal disease :
One of the emergency situations of Rheumatology consists of the Scleroderma renal crisis. This occurs with accelerated high blood pressure, rapid and progressive renal failure, microangiopathy and haemolysis, and a consumptive thrombocytopenia.
When there is associated  renal arterial spasm, and existing vessel abnormality, a reduction in renal bloodflow occurs - producing ischemia. Consequently, high blood Pressure results with a further reduction in renal bloodflow. Platelet and fibrin deposition occurs and microangiopathy with haemolysis results. Anaemia and thrombocytopenia are classical, with peripheral blood smear analysis, showing fragments. Prompt therapy of the blood pressure is essential to prevent progression to renal failure.

Scleroderma and pregnancy :
There is no association between pregnancy and the development of Scleroderma. Similarly pregnancy does not aggravate the disease itself. There is however, an association with impaired conception, and also growth retardation and low birth weight.

Endocrine abnormalities :
In one-third of cases, there is a tendency for the development of Sjogren Syndrome as a consequence of fibrosis of the salivary gland. There is a strong association with Sjogren patients and Anti- Ro and Anti- la Antibodies. This is characterized by dry eyes and dry mouth. Other glandular involvement includes an association with hypothyroidism and impotence.

The Antibody response :
Anti-Nuclear Antibodies are a typical finding in 90 percent of patients. The presence of AntiDNA antibody and Anti- Sm antibody are not seen in contrast to that of SLE.
Anti-nRNP -ribonucleoprotein, are seen in 20 percent of patients.

The more typical antibodies seen in Scleroderma are --

1. Anticentromere Antibodies.  these are found in up to 90 percent of patients with limited systemic sclerosis. In contrast, They are found in only 10 percent of patients with diffuse Scleroderma. The patients, who have limited Scleroderma, are more likely to have this antibody.
People with Raynauds phenomena, who have positive Anticentromere Antibodies, are more likely to develop limited Scleroderma.

2. Anti- Scl-70 antibodies. This is the antibody to the topoisomerase-1 antigen. Topoisomerase-1 is involved in the uncoiling of DNA doing transcription. It is seen in up to 40 percent of patients with diffuse Scleroderma. It is not usually seen in limited Scleroderma.

3. Other antibodies, including Rheumatoid factors may be seen in a small percentage of patients and Anti- Ro and Anti-La antibodies can be seen in those patients with Sjogren Syndrome.

Investigations in patients with systemic sclerosis.

The diagnosis is a clinical one, based on the history and the examination. The Antibodies may be useful especially the Anti- Scl-70 and the Anticentromere antibody. However a bedside technique of nailfold capillary examination reveals an abnormal nailfold capillary network. This is of predictive value in patients with Raynauds phenomena. Those patients with abnormal nailfold capillaries have a much greater risk of developing Scleroderma subsequently.
Other investigations are dependent on the clinical complaint -- including Barium Swallow, endoscopy, and studies of the small and large bowel with small and large bowel barium enema.
The differential diagnosis of the skin changes of Scleroderma includes linear Scleroderma, with localized bands of skin thickening and erythema, with regional atrophy of the sub-cutaneous tissues. Morphea is seen as a plaque of erythematosus lesions with central hypopigmentation. Eosinophilic fasciitis is characterized by a shiny and erythematosus rash usually involving the dermis of the forearms and legs, and occasionally the hands and trunk. There is inflammation of the dermis with thickening. Biopsy however shows an infiltrate of eosinophils.

Therapy and treatment of systemic sclerosis :

The therapy is determined upon the individual patient, the degree of skin involvement, and the presence or absence of internal organ involvement and complications. In particular, symptomatic therapy is required for the therapy of Raynauds phenomena and the esophageal problems and musculoskeletal symptoms. However it is important to assess patients for the need for disease modifying agents.

The therapy of Raynauds phenomenon is outlined elsewhere on the website, but includes careful use of gloves and hand warmers, the avoidance of cold where possible, and also use of warm socks to protect the feet from cold.
Vasodilator therapy, especially nifedipine or other Calcium channel blockers may be of help.
Topical Glyceryl trinitrate therapy may also be used.
In severe cases Ketanserin, an anti-serotonin drug, may be used.
Prostacycline trials have shown benefits for these patients.
Sympathetic nerve blocks have been used in potentially gangrenous digits. However sympathetic blockade is not felt to be the therapy of choice for mild Raynauds phenomenon.

Where there is digital ulceration, colchicine has been used in some studies showing benefit, and I personally use this frequently with good effect. It is important to treat any local Infection, with appropriate antibiotics and antiseptic solutions.
Surgical debridement may be required, but amputation should be avoided.

General treatment of the skin disease :
D- penicillamine was demonstrated in daily studies to improve skin thickening and also appeared to improve overall outcome. However it would appear that the results are best achieved when the drug is used early. The drug he has an anti-fibroblast effect.Gamma interferon has also and studies now been shown to inhibit fibroblast proliferation, and to reduce deterioration of the skin disease in some patients.
Colchicine has been also shown in some studies to reduce skin thickening when used early on, in the course of the disease.

The toxicicty profile of Penicillamine includes :

Minor side effects:
Skinrash and dermatitis in 25 percent
Anorexia, nausea, vomiting and diarrhoea, in 25 percent

Serious side effects however include:
Thrombocytopenia, in 10 percent
Proteinuria, as it results in a renal glomerulonephritis in 10 percent
Neutropenia or even aplastic anaemia

Very rare side effects include
Myaesthenia
Polymyositis
Good Pastures Syndrome
Systemic Lupus Erythematosus.

Therefore routine checks of the blood count and Urine analysis is essential.

Therapy of Calcinosis :
The development of calcification under the skin, and in the soft tissues is a major problem in some patients. Several remedies are described, with a variable results. Amongst those treatments suggested perhaps the most well known is low dose warfarin therapy 1mg / day. However colchicine and probenecid have also been used. Bisphosphonate drugs also offer a potential for treatment of extra articular calcification.

My personal preference is to use colchicine at a dose of 0.5 mg three times daily, but reduce the dose to twice a day, if the patient develops diarrhoea. In addition, I introduce penicillamine at a dose of 150 mg per day, increasing to 250 mg after one week, 500 mg after one month, and up to a maintenance dose of 750 mg after three months.
I then maintain the drug indefinitely, unless there is toxicity or loss of efficacy.

Treatment of the joints and Musculoskeletal System
The use of analgesics and Non Steroidal Anti-inflammatory drugs -- NSAID's, are usually required for relief of symptoms. However, low dose Prednisone-7.5 mg, is occasionally used for the treatment of symptoms that are refractory to standard Anti-inflammatory drugs.

Physical therapy and occupational therapy our essential to prevent contractures.
Exercise programs are extremely important to maintain mobility.

Treatment of the gastrointestinal manifestations.
Esophageal dysmotility is treated with medications to improve esophageal contraction and stomach emptying. The drug of choice for this, is metoclopramide [maxolon] and a dose of 10 mg three times a day as required prior to meals. Another option is cisapride [Prepulsid], and a dose of 10 mg three times the day is required, prior to meals. If necessary both maxolon and Prepulsid can be used. If however the esophageal reflux is a major problem, then proton pump inhibitor drugs, such as omeprazole [Prilosec] are extremely useful. If stricture of the esophagus has occurred, then dilatation of the lower esophagus may be the required.
Involvement of the small and large bowel with pseudo-obstruction is also notoriously difficult to treat. Surgery should be avoided. I have found Reye's solution to be of use in this situation. Antibiotics may be required for bacterial over growth producing malabsorption and diarrhea. Nutritional supplements to maintain body weight and general nutrition are vital.

Therapy of the pulmonary manifestations of Scleroderma.
Pulmonary involvement may arise from several mechanisms. The most common problem is that of progressive interstitial lung involvement. However, pulmonary hypertension is a major problem that arises, either as a primary or secondary problem. In addition, aspiration pneumonia as a consequence of the esophageal dysmotility needs to be guarded against and be treated promptly. Clinically the patient presents with insidious onset of breathlessness and cough.
To differentiate between interstitial lung disease and vascular disease with pulmonary hypertension, pulmonary testing, testing lung volumes and diffusion capacity, and high-resolution CT Scan, are sensitive for diagnosing interstitial lung disease. Echocardiography and Doppler are the methods of choice for diagnosis of pulmonary hypertension.
Very occasionally cardiac catheterization is required.

Pulmonary function tests are indicated six monthly. For those patients with interstitial lung disease, a combination of cortisone and immunosupression, are indicated on an individual case basis. The dose of Prednisone is 1.0 mg per kg and the immunosupression of choice is cyclophosphamide at a dose of 2 mg per kg per day. Appropriate monitoring for toxicity of these drugs is required.

For patients with pulmonary hypertension vasodilators including calcium channel blockers such as nifedipine or Diltiazem may reduce the pulmonary pressures. Other drugs that have been used in the past include hydrallazine.

Bosentan is now used in pulmonary hypertension.  This is a dual endothelin receptor antagonist and a potent vasodilator dropping pulmonary pressures. The drug however requires monitoring of liver unction. The commercial name is Tracleer. This drug is not available in South Africa yet.

There is no clear evidence that preventive therapy may prevent development of pulmonary involvement of Scleroderma. In fact, penicillamine itself has been a rare course of a pneumonitis.

Therapy of renal disease.
Renal disease is closely associated with hypertension problems. Successful management requires a progressive management of the blood pressure, aiming at complete normalization. Pathology in the kidney reveals blood vessel changes of intimal proliferation medial thinning and fibrinoid necrosis. Biochemistry reveals elevated plasma renin. Therefore angiotensin converting enzyme inhibitors have proven invaluable, in the treatment of Scleroderma renal crisis, and hypertension related complications. It is important to ensure that hypotension does not develop with vasodilator therapy. Uncontrolled blood pressure and in particular malignant hypertension may lead to renal failure with anuria. Renal dialysis may be required, and transplantation if irreversible. There is no indication for steroid therapy. Fifty percent of patients, who are on short-term dialysis, eventually manage to get off dialysis.

Pregnancy and systemic sclerosis :
There is a reduction in fertility associated with systemic sclerosis.
There is no clear aggravation of the disease by the pregnancy itself. There is however, a slightly increased incidence of toxaemia of pregnancy, and pregnancy induced hypertension.
Preexisting restrictive lung disease may be aggravated in later stages of the pregnancy.
There is in increased incidence of fetal loss and spontaneous abortions compared to normal pregnancies. Intra-uterine growth retardation is also increased.
The main aim of therapy is to ensure that the blood Pressure remains well controlled throughout the pregnancy. Angiotensin converting enzyme inhibitors are potentially teratogenic. Despite this, they are still used in Scleroderma renal crisis. Pulmonary disease is treated with steroids without cyclophosphamide. D- penicillamine is also potentially teratogenic and cannot be used during pregnancy. In general angiotensin converting enzyme inhibitors should not be used except in the circumstance of renal crisis.

Back to top of page

Scleroderma for the layman :

A description aimed at the patients' level of understanding :

Systemic sclerosis is a condition characterized by progressive fibrosis and thickening of the skin with progressive contraction, and also involving internal organs, especially blood vessels, joints, muscles, and heart, lung, kidney and bowel.
The problem was first thought and described as being a skin disease, but in fact in 1945 from autopsy research, Goetz described visceral or internal organ involvement, and he introduced the name progressive systemic sclerosis.

Various forms were identified. These were :

Generalized Scleroderma, where there is involvement proximal to the hands and a greater chance of rapid progressive internal organ involvement.

Localized Scleroderma, where the problem was restricted to the hands itself and its skin manifestations predominate. Internal organ involvement is slower to develop.

The problem occurs especially in the 40's, and there is a progressive thickening of skin with scar tissue developing generally within the skin itself. The skin ultimately begins to have areas of increased and decreased pigmentation. In the limited variety a Syndrome called CREST is described, this includes

Calcinosis -- calcification in the skin.

Raynauds phenomenon -- a colour sequence from pale and white, to blue to red, especially in the hands, in particular on exposure to cold and sometimes stress.

Esophageal dysmotility disorder -- presenting as difficulty swallowing.

Sclerodactyly -- where there is thinning and tightening of the tissue around the digits and a tightening of the skin in the hands and fingers.

Telangiectasia -- this is the appearance of blood vessel marks distributed around the eyes and the mucous membranes and the skin itself, especially on the face and chest wall.

The clinical manifestations include dysphagia -- because of esophageal problems, and the patient complains of food getting "stuck" and the patient  is unable to swallow effectively.  He finds it impossible to swallow solid foods and requires eating liquids or soft food and to sit upright or stand. This can be helped by the use of maxolon or Prepulsid.

Involvement of the small and large bowel may produced problems of constipation, discomfort and diarrhea and requires a generally softer, rather than a high fiber diet.

Involvement of the muscles is associated with a mild inflammation and a greater tendency to fibrosis with scarring and progressive infiltration of scar tissue within the muscles. Progressive weakening results. The patient finds it more difficult to get up out of a chair, because of this.

The involvement of joints causes pain and discomfort with minimal swelling in the joints themselves. There is a much smaller tendency for damage within in the joints. The main functional impairment arises because of contraction of the skin around the joints. Therefore it is important that exercise be done regularly to maintain function and prevent contractures.

Involvement of the lung is seen either from the elevated pressures of the blood vessels or from a scarring and inflammation of the lung tissue itself. This is on an immune basis. Severe inflammatory involvement of the lung tissue, is treated aggressively with cortisone and possibly the used of cyclophosphamide or immunosupression.

The involvement of the heart occurs with fibrosis of the muscle, and conducting tissues with in the heart. This causes increased or decreased heart rate abnormalities.

A general reduction in function of the heart muscle may also be a problem, and can produced heart failure.

The involvement of the kidney is centralized on the effects of blood Pressure, and the spasm of the walls of the blood vessels in the kidney. If the some rapid development of high blood Pressure because of spasm and blood vessel involvement in the kidney, may result in the condition called Scleroderma renal crisis. This is one of the emergencies in rheumatology. In the days prior to therapy 90 percent of patients with Scleroderma kidney and renal crisis would die, however, today, we treat the blood Pressure aggressively with angiotensin converting enzyme inhibitors, the aim being full and rapid blood pressure control.

The effects of Scleroderma are progressive and tend to be disabling, and it is felt that early introduction of therapy may result in a better prognosis. If the skin is already severely affected, there is very little that will reverse of the progression. However, if therapy is introduced early, outcome may well be improved.

In an early phase, the skin goes through a phase of oedema and swelling. This stage treated with corticosteroids. However, once this stage is passed, corticosteroids have little place. The main type of therapy is D-penicillamine, but some people also use colchicine. Other forms of research have included the use of gamma interferon, which has been shown in some studies to improve the skin. Penicillamine does not help the lung progression, or internal organ involvement.

Using vasodilator drugs reduces the pulmonary pressures, and the pulmonary interstitial disease itself is treated, by the use of cortisone with or without immunosuppression, depending on the degree of active inflammation and progression.

The esophageal and bowel contraction problems are treated with therapies aimed at increasing the muscle contraction. In addition, whilst antacids may be useful, we generally use proton pump inhibitors for the problem, as reflux of acid back into the esophagus may cause complications of esophageal ulceration or even aspiration pneumonia.

The muscle disease itself may require steroids if there is active inflammation. Joint involvement may require Anti-inflammatory drugs and analgesics.

Physiotherapy and occupational therapy are important to increase strength and maintain function.