NORD gratefully acknowledges Etienne Leveille, MD Candidate, McGill University School of Medicine, and John Varga, MD, John and Nancy Hughes Distinguished Professor in the Division of Rheumatology; Director of the Scleroderma Program, Northwestern University Feinberg School of Medicine, for assistance in the preparation of this report.
Systemic scleroderma is a disease characterized by rapid growth of fibrous (connective) tissue that leads to scarring of skin and internal organs. Approximately one in 10,000 individuals is affected. It is more common in women and most often develops around age 30 to 50. Systemic scleroderma can affect almost any organ in the body, and there is a large variability of symptoms among affected individuals. One of the most common and earliest manifestations of the disease is Raynaud phenomenon, which involves blood vessel spasms (vasospasms) induced by cold temperature or stress. This can lead to temporary finger discoloration, numbness and pain and is also associated with the development of finger ulcers. Of note, Raynaud phenomenon also commonly occurs in healthy individuals. Other manifestations of systemic scleroderma include muscle and joint pain, skin tightening, and dilated blood vessels that can be seen through the skin (telangiectasias). Scarring of internal organs can also lead to gastrointestinal, pulmonary, cardiac, and renal disease. Although systemic scleroderma cannot be cured, many of the symptoms can be treated. A timely diagnosis is important to ensure appropriate management of the disease and associated complications.
Systemic scleroderma can affect multiple organ systems and therefore lead to numerous symptoms and complications. The symptoms present, their severity, the rate of progression of the disease, the response to treatment, and overall survival vary widely depending on the affected individual. In most cases, people start to develop symptoms between age 30 and 50. Symptoms related to the different organs involved are described below.
In most people, Raynaud phenomenon (RP) is the first manifestation of the disease. RP is characterized by blood vessel spams (vasospasm) in response to cold or stress. This most often occurs in the fingers and turns them white. Subsequently, as the vessels are occluded and cannot deliver oxygen, the fingers turn blue. This can also lead to severe pain and ulcers. After several minutes (usually 15 to 20), the vasospasms stop and the fingers become red as blood flows again. Another very common symptom of systemic scleroderma is rapid growth of connective tissue in the skin (skin fibrosis). The earliest involved areas are the fingers, hands and face. Symptoms associated with skin fibrosis include tight and dry skin, itching (pruritus), fluid accumulation (edema) and increased or decreased skin pigmentation. Another skin manifestation seen in most patients with scleroderma is telangiectasia. Telangiectasias are small dilated blood vessels that can appear as red lesions visible through the skin. Affected individuals can also develop accumulation of calcium nodules in the fingers, forearm, elbows, and knees. This condition is known as calcinosis cutis and can lead to pain if the nodules are large.
Nerves, muscles, and joints
Many individuals living with systemic scleroderma develop muscle, joint, or nerve disease. Muscle involvement can lead to muscle pain, weakness, and muscle wasting (sarcopenia). Affected joints can be painful, stiff, and swollen. Nerve involvement is less common but can lead to burning or tingling sensation or numbness. In some individuals, the autonomic nervous system can be affected. This part of the nervous system is not under voluntarily control and is notably involved in self-regulation of the body. Dysfunction of the autonomic nervous system can lead to symptoms such as dizziness when standing up (orthostasis), inappropriate heart rate response to exertion, and inappropriate sweating.
The two main pulmonary manifestations of systemic scleroderma are pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD). PAH is defined as increased pressure in the arteries of the lungs and can lead to shortness of breath (dyspnea), fatigue, and failure of the right ventricle of the heart, which in turn can cause chest pain, fluid accumulation (edema), and transient loss of consciousness upon exertion (exertional syncope). ILD corresponds to scarring (fibrosis) of lung tissue, which prevents lung expansion and gas exchange. The two main symptoms of ILD are progressive dyspnea and dry cough. PAH and ILD are progressive conditions and can eventually become life-threatening. Taken together, they account for about half of all deaths related to systemic scleroderma.
The most commonly involved part of the gastrointestinal tract in systemic scleroderma is the esophagus. In affected individuals, the esophagus is unable to contract efficiently (esophageal dismotility) to allow food to reach the stomach. In addition, the lower esophageal sphincter (LES), which is a circular muscle between the esophagus and the stomach, is not able to close properly. The combination of esophageal dismotility and LES incompetence can lead to heartburn due to acid reflux (a condition known as gastroesophageal reflux disease; GERD), choking on food, and difficulty swallowing (dysphagia). Fibrosis of the rest of the gastrointestinal can prevent food from moving through properly (pseudo-obstruction), which can promote bacterial growth and lead to pain, bloating, constipation, diarrhea, and fecal incontinence. Gastrointestinal bleeding also occurs in some patients due to dilation of veins in the stomach (gastric venous ectasias).
Systemic scleroderma can affect many parts of the heart, including the heart muscle itself (myocardium), the sac in which it is contained (pericardium), the arteries feeding it (coronary arteries and arterioles), and its electrical conduction system. The manifestations of cardiac involvement vary depending on the affected part of the heart and can include chest pain, shortness of breath, hearth rhythm abnormalities (arrhythmias) and inability of the heart to pump blood forward optimally (heart failure).
The most significant renal manifestation of systemic scleroderma is scleroderma renal crisis (SRC). It is characterized by abrupt onset on severe high blood pressure (hypertension), renal failure, and abnormal protein excretion in the urine (proteinuria). Another feature of SRC is microangiopathic hemolytic anemia (MAHA). In this condition, the platelets present in the blood excessively form clots in small vessels. When red blood cells travel in these vessels, they get sheared by the platelet clots (hemolysis). MAHA therefore leads to a decreased number of red blood cells (anemia) and platelets (thrombocytopenia).
In addition to symptoms described above, people living with systemic scleroderma commonly experience fatigue, anxiety, sexual dysfunction and concerns with body image. Although the disease is potentially fatal and is associated with an increased risk of mortality, many affected individuals can live long, productive lives.
Systemic scleroderma is typically divided in four subsets with different clusters of symptoms. Limited cutaneous systemic sclerosis (lcSSc) is associated with skin fibrosis limited to the hands, forearm, feet and face, and usually prominent telangiectasias and calcinosis cutis. People with lcSSc can develop pulmonary arterial hypertension but very rarely develop scleroderma renal crisis and interstitial lung disease. Diffuse cutaneous systemic sclerosis is associated with rapid and diffuse skin fibrosis and early occurrence of renal, cardiac, and pulmonary complications. Systemic sclerosis sine scleroderma involves internal organ involvement of systemic scleroderma without the typical skin involvement. Systemic scleroderma overlap syndrome includes features of other connective tissue diseases such as rheumatoid arthritis or polymyositis and is notable for prominent joint and muscle involvement. Distinguishing the clinical subset of systemic scleroderma in an affected person is important as it can help predict the progression of the disease and the associated complications. However, not all patients fall within a specific subset and overlap between different categories is common.
Although the exact cause and disease mechanism of systemic scleroderma are not known, it is thought to occur in genetically predisposed individuals following a trigger, possibly exposure to virus or toxins. Systemic scleroderma is an autoimmune disease, which means that it involves a dysregulated immune system that attacks the affected individual’s own body. The first event to occur is possibly injury to small blood vessels (microvascular injury). In healthy individuals, response to injury leads to recruitment of inflammatory mediators that facilitate repair. In individuals with systemic scleroderma, microvascular injury leads to disproportionate inflammatory mediator recruitment and excessive fibrous tissue deposition. This fibrous tissue can replace healthy tissue and lead to symptoms of systemic scleroderma such as skin thickening, internal organ scarring and associated complications.
Systemic scleroderma affects between 38 and 341 individuals per million throughout the world (prevalence) and develops in 8 to 56 individuals per million each year (incidence). It is more common in populations from southern Europe, North America and Australia, and less common in populations from northern Europe and Japan. The disease most often starts to manifest in the fifth decade of life (age of onset). Although it most commonly occurs in women, men tend to have more severe disease. African American individuals tend to have a lower age of onset, higher rates of the diffuse cutaneous subtype, and overall more severe disease.
Systemic scleroderma is a complex disorder that can be difficult to diagnose. In most cases, the diagnosis starts with a complete patient history and physical examination. If systemic scleroderma is suspected, laboratories test can be ordered. Notably, certain antibodies reacting against components of an individual’s body (autoantibodies) can be identified in systemic scleroderma. Antinuclear antibodies are present in approximately 95% of individuals. However, they are also present in other autoimmune conditions and in healthy individuals. Antitopoisomerase I (anti-Scl-70) antibodies and anti-RNA polymerase III antibodies are associated with dcSSc, while anticentromere antibodies can be seen in lcSSc. If antibodies titers are indicative of systemic scleroderma, specific tests will be performed to confirm the diagnosis and evaluate for internal organ involvement. Pulmonary function tests (PFTs) are breathing tests used to assess the lungs capacity to move air and diffuse it to the blood. They are often complemented by a computed tomography (CT) scan of the chest to visually assess the structure of the lungs. The heart and pulmonary arteries can be imaged with cardiac echocardiography, which uses ultrasound waves to reconstruct and visualize anatomical structures. Renal function can notably be evaluated by measuring creatinine levels in the blood and by urine analysis. Further testing might be indicated depending on the symptoms and characteristics of the affected individual.
Treatment & Management
As there is no cure for systemic scleroderma, management of the disease is mostly centered on symptom control and screening to detect and better control complications. Patients usually require long-term regular follow-up with numerous medical specialists. As systemic scleroderma is an autoimmune disease, medications that suppress the immune system (immunosuppressants) can be used, especially in severe cases with diffuse skin involvement, interstitial lung disease, inflammation of the heart muscle (myocarditis) and severe muscle or joint inflammation. Immunosuppressants used in systemic scleroderma include methotrexate, mycophenolate mofetil (MMF), and azathioprine. Glucocorticoids such as prednisone are also occasionally used in some patients, but their use is generally avoided if possible due to the risk of side effects.
Skin, muscles, joints, and nerve
As mentioned above, patients with widespread skin involvement or severe muscle or joint inflammation might benefit from immunosuppressants. Those with Raynaud phenomenon are most commonly treated with calcium channel blockers such as Norvasc (amlodipine) and Procardia XL (nifedipine). Calcinosis cutis might be managed with a class of medications known as bisphosphonates, which are often used for the treatment of osteoporosis, while larger calcium deposits might need to be removed surgically. Pigmentary changes such as telangiectasias can be treated with laser therapy. Rheumatologists will be involved in the management of these symptoms, and dermatologists can contribute to the treatment of skin disease. Neurologists might also be involved to evaluate and treat neurologic complications of the disease. For instance, pain medication such as Lyrica (pregabalin) or Neurontin (gabapentin) can be prescribed in patient with burning pain because of nerve damage (neuropathic pain).
Early recognition of interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) with appropriate diagnostic methods (described in the “diagnosis” section) are crucial to initiate treatment as soon as possible. ILD has traditionally been treated with immunosuppressants. In 2019, Ofev (nintedanib) was approved by the Food and Drug Administration (FDA) to slow the rate of decline in pulmonary function in adults with ILD associated with systemic scleroderma (SSc-ILD). PAH is mainly treated with medication, such as Flolan (epoprostenol) or Tracleer (bosentan) that aims to decrease the constriction of pulmonary arteries. Respirologists are physicians that will manage the respiratory complications of individuals living with systemic scleroderma. Surgeons will also be part of the treating team in cases of very severe pulmonary disease, where lung transplantation can be considered.
The majority of patients with systemic scleroderma are treated with medication, such as Protonix (pantoprazole), that decreases acid production by the stomach. Some patients are also prescribed medication that increase gastrointestinal motility such as Reglan (metoclopramide) or Motilium (domperidone). Antibiotics can be used in patients with gastrointestinal bacterial overgrowth and associated symptoms. Gastroenterologists will often be involved, especially if other gastrointestinal manifestations that require more specific treatments are present.
The treatment of systemic scleroderma-associated cardiac disease will depend on the specific cardiac manifestation that is present. Heart failure might require a specific kind of medication, known as ACE inhibitors (for instance, perindopril), that is used for high blood pressure, and medications that make the patient urinate (diuretics), such as Lasix (furosemide), to decrease fluid overload. As described above, immunosuppressants can be used in individuals with myocarditis. Cardiologists are the physician that will follow systemic scleroderma patients to manage potential cardiac complications.
In addition to supportive management, ACE inhibitors are the mainstay of treatment for scleroderma renal crisis (SRC). Of note, chronic high doses of glucocorticoids are associated with an increased risk of SRC, which is another reason why their use is limited as much as possible in systemic scleroderma. In severe cases of SRC, dialysis and even renal transplantation might be required if renal function does not improve after the crisis. Nephrologists are physicians specialized in the diagnosis and management of kidney (renal) diseases.
Depending on the affected individual and their needs, other professionals will be involved such as nurses, social workers, physiotherapists, occupational therapists, and psychologists.
As the mechanisms responsible for the development and progression of the disease are uncovered, new medications or medications already on the market for other diseases are tested in clinical trials. Example of targeted therapies being investigated include rilonacept and tocilizumab, which respectively target IL-1 and IL-6, two inflammatory mediators thought to be important in systemic scleroderma.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
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