Scleroderma is a disabling disease where thick tissue forms around the cells of the skin and internal organs. Existing treatments relieve symptoms and limit damage. There are many research efforts into finding new medicines.
Scleroderma literally means “hard skin“. The name is derived from the Greek words “sklerosis“, meaning hardness, and “derma“, meaning skin. In scleroderma, collagen forms thick connective tissue that builds up around the cells of the skin and internal organs. Actually, scleroderma is one symptom of a cluster of disorders that involve the abnormal growth of connective tissue. In some forms, hard, tight skin is the extent of the abnormal process. In other forms, the disease affects blood vessels and internal organs, such as the heart, the lungs, and kidneys. Scleroderma is both a rheumatic and a connective tissue disease. The term “rheumatic“ characterises the inflammation and/or pain in the muscles, joints, or fibrous tissue. Connective tissue disorders affect the matrix compounds of the skin, the tendons, and the bones.
The cause of scleroderma is not known. It is not an infectious disease. Studies of twins suggest it is not inherited, and the disease is not passed from parents to children. So far, scientists believe that scleroderma is caused by several factors, such as abnormal activity of the immune system, genetic make-up, hormones and environmental influence. Research has shown that pregnancy increases a woman’s risk of scleroderma. Other findings suggest that exposure to environmental factors may trigger the disease in people who are genetically predisposed. Suspected triggers include viral infections, certain adhesive and coating materials, and organic solvents.
Scleroderma can be divided into two forms: localised scleroderma and systemic scleroderma. The localised form is limited to the skin and related tissues. Internal organs are not affected, and localised scleroderma does not progress to the systemic form. Often, localised conditions improve or disappear on their own over time, but the skin changes and damages may become permanent. Thus, localised scleroderma can be serious and disabling.
There are two types of localised scleroderma: morphea, which means “form“ or “structure“ in Greek, and linear scleroderma. Morphea refers to reddish patches of skin that thicken into firm, oval-shaped areas; most often on the chest, stomach and back. Morphea generally fades out in three to five years; however, patients are left with darkened skin patches and, in rare cases, muscle weakness. Linear scleroderma refers to the single line or band of thickened and abnormally coloured skin. The line may run down an arm or leg, but in some people it runs down the forehead. Dermatologists use the French term “en coup de sabre“, or “sabre stroke,“ to describe this phenomenon.
Systemic scleroderma involves the tissue layers surrounding the blood vessels and major organs. Patients have all or some of the symptoms that are described by the acronym CREST: (i) Calcinosis, which is a formation of calcium deposits in the connective tissues; (ii) Raynaud’s phenomenon: a condition in which the small blood vessels of the hands or feet contract in response to cold or anxiety; (iii) Esophageal dysfunction occurs when smooth muscles in the oesophagus lose normal movement; (iv) Sclerodactyly, which refers to thick and tight skin on the fingers, because of deposits of excess collagen within skin layers; and (v) Telangiectasias, which are small red spots on the hands and face that are caused by the widening of very small blood vessels.
Scleroderma is more common in women, but the disease also occurs in men and children. In the age group 30-55 years, women develop scleroderma at a rate 7-12 times higher than men. The disease affects people of all races and ethnic groups. However, there are some patterns by disease type. Localised forms are more common in Caucasians than in African Americans. Morphea usually appears between the ages of 20-40. Linear scleroderma mostly occurs in children or teenagers. Systemic scleroderma typically occurs in people from 30 to 50 years old. It affects more coloured women than white women.
Because systemic scleroderma can be difficult to diagnose, epidemiologists can only estimate how many cases there actually are. Estimates for the number of patients in Europe range between 40 and 200 adults per million inhabitants, which is equivalent to 16,000 to 80,000 cases. The five-year survival rate of patients with the systemic form of the disease is approximately 80 per cent.
Currently, there is no therapy that controls or inhibits the pathological production of collagen in scleroderma. Thus, therapy focuses on relieving symptoms and limiting damage. Pain-killers and non-steroidal anti-inflammatory drugs (NSAID) are used to ease joint inflammation or muscle pain. Oil-based creams and lotions are applied to soften the hardened skin. For the treatment of heartburn, medicines of the group of proton pump inhibitors or H₂-antagonists are used.
About 10-15 per cent of patients with systemic scleroderma develop either pulmonary fibrosis (hardening of lung tissue because of excess collagen) or pulmonary hypertension (high blood pressure in the artery that carries blood from the heart to the lungs). Pulmonary fibrosis is treated with immunosuppressant compounds, along with low doses of corticosteroids. Pulmonary hypertension is treated with medicines that dilate the blood vessels such as prostacyclins or 5-phosphodiesterase (5-PDE) inhibitors. For patients with heart problems, e.g. cardiomyopathy (scarring and weakening of the heart), myocarditis (inflammation of the heart muscle) or arrhythmia (abnormal heart beat), treatment options range from medicines to surgery. About 15-20 per cent of patients develop severe kidney problems. Medicines known as angiotensin-converting enzyme (ACE) inhibitors have made scleroderma-related kidney failure a less threatening problem than it was in the past.
Compounds that are capable of inhibiting fibroblast activity may be beneficial if administered early in the course of the disease. In a phase 1/2 clinical trial, investigators are assessing the effect of an endothelin-1 antagonist on disease progression. Endothelin-1 has several distinct properties, among them profibrotic and inflammatory activity, and vasoconstriction.
Researchers are studying the effect of a newly found imidazo-chinoline compound which induces cytokines that inhibit fibrotic activity. The compound is applied topically as five per cent cream in localised scleroderma. Main outcome of this phase 3 clinical trial will be improvement of skin hardening.
Early studies suggest relaxin, a hormone that helps a woman’s body to stretch to meet the demands of a growing pregnancy, may soften the connective tissues of women with scleroderma. The hormone is believed to work by inhibiting fibrosis.
Other research groups are investigating the effectiveness of various treatments, including: (i) combinations of immunosuppressant compounds; (ii) collagen peptides administered orally; (iii) a medicine which inhibits the synthesis of type I collagen, which is the primary component of connective tissue; (iv) ultraviolet light therapy for localised forms of scleroderma; and (v) stem cell transfusions, which represents a form of bone marrow transplant that uses a patient’s own cells, for early systemic scleroderma.
Scientists have found a gene associated with scleroderma in Choctaw Native Americans who develop the disease far more often than other people. The gene codes for a protein called fibrillin-1, and researchers believe that it may put people at risk for the disease.
The role of environmental factors and particularly exposure to certain compounds, has been suggested as a cause of scleroderma. This warrants large scale prospective, case-control studies. With financial support from the EU, the European League against Rheumatism (EULAR) has established the EUSTAR (EULAR Scleroderma Trials and Research Group) data bank, to lay the foundation for better cooperation between clinical and research centres dealing with the pathophysiology and aetiology of the disease. The network will strive to improve both patient care, and the clinical and basic research environment and infrastructure