Systemic sclerosis
Systemic sclerosis, also known as scleroderma, is a chronic autoimmune disorder characterized by excessive collagen deposition, leading to tissue hardening and scarring. The condition arises when the immune system mistakenly attacks the body’s own tissues, particularly affecting blood vessels and connective tissues. Initial symptoms often include Raynaud's phenomenon—where fingers whiten in response to cold—and progressive thickening of the skin, particularly on the hands and face. As systemic sclerosis advances, it can impact internal organs, leading to complications such as pulmonary hypertension, gastrointestinal issues, kidney damage, and heart failure.
Various factors appear to trigger systemic sclerosis, including environmental exposures (like silica and certain chemicals), genetic predispositions, and viral infections. The disease is more prevalent in women, particularly among African American and American Indian populations. Treatment is focused on managing symptoms and slowing the progression of fibrosis, employing medications such as immunosuppressants and anti-inflammatory drugs. Recent advancements, including hematopoietic stem cell transplantation, show promise in improving patient outcomes. Understanding systemic sclerosis is crucial for effective management and support for those affected by this complex condition.
Systemic sclerosis
Disease/Disorder
Also known as: Systemic scleroderma
Anatomy or system affected: All
Definition: A systemic disease characterized by extensive scarring in the skin, connective tissue, and internal organs.
Key terms:
autoimmune response: an inappropriate immune response against the patient's own cells
cytokines: small proteins released by immune cells that elicit specific effects from other cells
fibroblast: an immature cell that manufactures connective tissues
fibrosis: an increase in the fibrous scar tissue deposited between cells
Causes and Symptoms
During the process of wound healing, specific cells known as fibroblasts deposit a protein called collagen to heal the breach in our tissues. Large areas of collagen deposition compose what we commonly call a scar. Our bodies carefully regulate collagen deposition to prevent scarring in unneeded places. People with systemic sclerosis (SSc) experience unregulated deposition of collagen.
In SSc patients, the immune system malfunctions and attacks the body's own tissues and organs. This continuous damage and inflammation leads to continuous collagen deposition and scarring, which stiffens, hardens, and thickens those tissues and organs affected by the inflammation.
Typically, the SSc-specific autoimmune response begins with damage to blood vessels, which summons immune cells to the injury site. The immune cells secrete small signaling proteins called cytokines, in particular platelet-derived growth factor (PDGF), transforming growth factor-β1 (TGF-β1), and interleukin-6 (IL-6). These cytokines signal to antibody-producing B-lymphocytes to produce antibodies against blood vessels, and also signal to fibroblasts to differentiate into myofibroblasts. In response to the tissue destruction caused by the immune response, myofibroblasts deposit collagen and other molecules in an attempt to mitigate the damage. This repeated cycle of damage and collagen deposition leads to the formation of large, stiff scars that harden the tissue or organ and compromise its function.
What causes the initial damage to blood vessels remains unknown, but several factors seem to act as triggers. Exposure to silica, organic solvents (e.g., toluene, hexane, vinyl chloride, xylene, etc.), epoxy resins, pesticides, certain drugs (e.g., bleomycin cocaine, carbidopa, and others), appetite suppressants, silicone or paraffin implants, or vibrational injuries seem to act as triggers that initiate the cascade of events that lead to SSc. Genetic factors also clearly play a vital role in the propensity someone has to develop SSc. Finally, particular viral infections (e.g., cytomegalovirus) that infect and damage blood vessels might act as triggers.
Internationally, SSc afflicts 2.3-10 people per one million, and affects women three to six times more often than men. SSc is rare in Japan and China and more common in African American and American Indian women than in white women.
The first signs of SSc tend to be Raynaud's phenomenon or a whitening of the hands in response cold exposure, and itching (pruritus). Damage to blood vessels causes puffy, swollen hands. Afterwards, the skin begins to thicken and harden, usually beginning with the hands and face. Lack of blood flow to the hands can produce ulcers at the tips of the fingers. Also, calcium deposits form under the skin (calcinosis). Calcium deposits and thickening of the skin can restrict movement around joints, especially the smaller joints of the hand. Patients can also experience arthritis and muscle weakness.
Lung damage causes shortness of breath upon exertion and later also at rest. Elevation in blood pressures in the pulmonary arteries (pulmonary hypertension) follows. Scarring of the gastrointestinal tract usually begins with narrowing of the esophagus (peptic stricture), which causes difficulty swallowing (dysphagia), and increased scarring reduces gastrointestinal motility. Severe gastroesophageal reflux disease (GERD) follows, which predisposes the patient to esophageal cancer. Reduction in intestinal motility compromises nutrient absorption, leading to malnutrition.
In the kidney, SSc produces scleroderma renal cysts. Kidney involvement substantially raises blood pressure (malignant hypertension) and blood levels of ammonium (azotemia), and causes the leakage of blood (hematuria) and protein (proteinuria) into urine.
Heart involvement scars the heart, leading to life-threatening heart failure. Vascular damage can also induce strokes.
Those who suffer from limited cutaneous SSc usually experience symptoms restricted to the skin. However, those who have diffuse cutaneous SSc show rapid scarring (fibrosis) of the skin, and internal organs, in particular the lungs, heart, gastrointestinal tract, and kidneys.
Treatment and Therapy
Serological tests of blood from SSc patients typically reveal particular auto-antibodies or antibodies that bind to patient's own tissues; antinuclear antibodies are characteristic of SSc. Imaging studies can document the fibrotic changes in the lungs, heart, and gastrointestinal tract, as can histological examinations of biopsied tissues.
Treatment focuses on decreasing fibrosis and preserving organ function. To stifle fibrosis, antiscarring drugs such as D-penicillamine, interferon-α, interferon-γ, methotrexate, chlorambucil, cyclosporine, thalidomide, tacrolimus, corticosteroids, cyclophosphamide, and statins have provided some patients relief, albeit not consistently. For patients with gastrointestinal involvement, proton pump inhibitors and H2 receptor blockers can control the symptoms of GERD. To treat inflammation of muscles, high dose corticosteroids can halt the advance of fibrosis. In patients with lung involvement, calcium-channel blockers, prostaglandins such as prostacyclin, and cyclophosphamide have provided relief for some, though not all, patients. For those with kidney involvement, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers are essential to control hypertension. For Raynaud's phenomenon, avoiding exposure to cold temperature and warm clothing can prevent the onset of symptoms.
Pulsed dye laser treatments can effectively clear fibrotic areas, but multiple treatments are required and recurrence remains a problem.
Procedures and Prospects
Early paintings and written descriptions possibly recount cases of SSc, but the first codified description of SSc comes from Carlo Curzio in 1752. Curzio treated a seventeen-year-old woman at the Royal Hospital in Naples who suffered from a diffuse hardness of her skin. The Milanese physician Giovambattista Fantonetti in 1836 was the first to use the term “scleroderma,” which comes from a combination of the Greek words “skleros” or hard and “dermos” or skin. Fantonetti described a thirty-year-old patient named Antonia Alessandri whose skin was as dark, tense, and firm as leather. Fortunately, Ms. Alessandri miraculously recovered three months later, which casts doubt on Fantonetti's diagnosis, but medical professionals continued to use the term he coined.
Perhaps the most exciting development in SSc is the use of bone marrow stem cell transplantations to treat SSc patients. Patients treated with hematopoietic stem cell transplantations (HSCTs) survive better, have significantly improved skin flexibility, and some improvements in lung function. Refining this procedure should make it more mainstream rather than experimental.
Bibliography
Hajj-ali, Rula A. "Systemic Sclerosis." Merck Manual. Merck, Aug. 2013. Web. 18 Mar. 2015.
Jacob, Elliot, ed. Medifocus Guidebook on: Scleroderma. Silver Spring: Medifocus, 2013. Print.
Khanna, Dinesh, George E. Georges, and Daniel R. Couriel. "Autologous Hematopoietic Stem Cell Therapy in Severe Systemic Sclerosis: Ready for Clinical Practice?" Journal of the American Medical Association 311.24 (2014): 2485–487. Print.
Onishi, Akira, Daisuke Sugiyama, Shunichi Kumagai, and Akio Morinobu. "Cancer Incidence in Systemic Sclerosis: Meta-Analysis of Population-Based Cohort Studies." Arthritis and Rheumatism 65.7 (2013): 1913–921. Print.
"Systemic Scleroderma." Genetics Home Reference. Natl. Inst. of Health, Sept. 2011. Web. 18 Mar. 2015.