| Systemic scleroderma | |
|---|---|
| Other names | Diffuse scleroderma, systemic sclerosis, Curzio's Syndrome |
.jpg) | |
| Patient with systemic scleroderma | |
| Specialty | Rheumatology  |
Systemicscleroderma, orsystemic sclerosis, is anautoimmunerheumatic disease characterised by excessive production and accumulation ofcollagen, calledfibrosis, in the skin and internal organs and by injuries to smallarteries. There are two major subgroups of systemic sclerosis based on the extent of skin involvement: limited and diffuse. The limited form affects areas below, but not above, the elbows and knees with or without involvement of the face. The diffuse form also affects the skin above the elbows and knees and can also spread to thetorso.Visceral organs, including thekidneys,heart,lungs, andgastrointestinal tract can also be affected by the fibrotic process.Prognosis is determined by the form of the disease and the extent of visceral involvement. Patients with limited systemic sclerosis have a better prognosis than those with the diffuse form. Death is most often caused by lung, heart, and kidney involvement. The risk ofcancer is increased slightly.[1]
Survival rates have greatly increased with effective treatment forkidney failure. Therapies includeimmunosuppressive drugs, and in some cases,glucocorticoids.[2]
Calcinosis,Raynaud's phenomenon,Esophageal dysfunction,Sclerodactyly, andTelangiectasia (CREST syndrome) are associated with limited scleroderma. Other symptoms include:
.jpg)
In the skin, systemic sclerosis causes hardening and scarring. The skin may appear tight, reddish, or scaly. Blood vessels may also be more visible. Where large areas are affected, fat and muscle wastage may weaken limbs and affect appearance. Patients report severe and recurrentitching of large skin areas. The severity of these symptoms varies greatly among patients: Some having scleroderma of only a limited area of the skin (such as the fingers) and little involvement of the underlying tissue, while others have progressive skin involvement.[3] Digital ulcers—open wounds especially on fingertips and less commonly the knuckles—are not uncommon.[4]
Diffuse scleroderma can causemusculoskeletal, pulmonary, gastrointestinal, renal, and other complications.[5] Patients with greater cutaneous involvement are more likely to have involvement of the internal tissues and organs. Most patients (over 80%) have vascular symptoms and Raynaud's phenomenon, which leads to attacks of discoloration of the hands and feet in response to cold. Raynaud's normally affects the fingers and toes. Systemic scleroderma and Raynaud's can cause painful ulcers on the fingers or toes, which are known as digital ulcers. Calcinosis (deposition of calcium in lumps under the skin) is also common in systemic scleroderma, and is often seen near the elbows, knees, or otherjoints.[6]
The first joint symptoms that patients with scleroderma have are typically nonspecificjoint pains, which can lead toarthritis, or cause discomfort intendons ormuscles.[5] Joint mobility, especially of the small joints of the hand, may be restricted by calcinosis or skin thickening.[7] Patients may develop muscle weakness, ormyopathy, either from the disease or its treatments.[8]
Some impairment in lung function is almost universally seen in patients with diffuse scleroderma onpulmonary function testing,[9] but it does not necessarily cause symptoms, such as shortness of breath. Some patients can developpulmonary hypertension, or elevation in the pressures of thepulmonary arteries. This can be progressive, and can lead to right-sidedheart failure. The earliest manifestation of this may be a decreaseddiffusion capacity on pulmonary function testing.[citation needed] Other pulmonary complications in more advanced disease includeaspiration pneumonia,pulmonary hemorrhage andpneumothorax.[5]
Diffuse scleroderma can affect any part of the gastrointestinal tract.[10] The most common manifestation in the esophagus is refluxesophagitis, which may be complicated byesophageal strictures or benign narrowing of the esophagus.[11] This is best initially treated withproton pump inhibitors for acid suppression,[12] but may requirebougie dilatation in the case of stricture.[10]
Scleroderma can decreasemotility anywhere in the gastrointestinal tract.[10] The most common source of decreased motility is the esophagus and the lower esophageal sphincter, leading to dysphagia and chest pain. As scleroderma progresses, esophageal involvement from abnormalities in decreased motility may worsen due to progressive fibrosis (scarring). If this is left untreated, acid from the stomach can back up into the esophagus, causing esophagitis andgastroesophageal reflux disease. Further scarring from acid damage to the lower esophagus many times leads to the development of fibrotic narrowing, also known as strictures, which can be treated by dilatation[citation needed].
In patients with neuromuscular disorders, particularly progressive systemic sclerosis and visceral myopathy, theduodenum is frequently involved.[13] Dilatation may occur, which is often more pronounced in the second, third, and fourth parts. The dilated duodenum may be slow to empty, and the grossly dilated, atonic organ may produce a sump effect.[citation needed]
Thesmall intestine can also become involved, leading tobacterial overgrowth andmalabsorption ofbile salts,fats,carbohydrates,proteins, andvitamins. Thecolon can be involved, and can causepseudo-obstruction orischemic colitis.[5]
Rarer complications includepneumatosis cystoides intestinalis, or gas pockets in the bowel wall,wide-mouthed diverticula in the colon and esophagus, andliver fibrosis. Patients with severe gastrointestinal involvement can become profoundlymalnourished.[11]
Scleroderma may also be associated withgastric antral vascular ectasia, also known as "watermelon stomach". This is a condition in which atypical blood vessels proliferate, usually in a radially symmetric pattern around thepylorus of the stomach. It can be a cause ofupper gastrointestinal bleeding oriron-deficiency anemia in patients with scleroderma.[11]
Kidney involvement, in scleroderma, is considered a poor prognostic factor and frequently a cause of death.[14]
The most important clinical complication of scleroderma involving the kidney is scleroderma renal crisis (SRC), the symptoms of which aremalignant hypertension (high blood pressure with evidence of acute organ damage),hyperreninemia (high renin levels),azotemia (kidney failure with accumulation of waste products in the blood), andmicroangiopathic hemolytic anemia (destruction of red blood cells).[15] Apart from the high blood pressure,hematuria (blood in the urine) andproteinuria (protein loss in the urine) may be indicative of SRC.[16]
In the past, SRC was almost uniformly fatal.[17] While outcomes have improved significantly with the use ofACE inhibitors,[18][19] the prognosis is often guarded, as a significant number of patients are refractory to treatment and developkidney failure. About 7–9% of all diffuse cutaneous scleroderma patients develop renal crisis at some point in the course of their disease.[20][21] Patients who have rapid skin involvement have the highest risk of renal complications.[22] It is most common in diffuse cutaneous scleroderma, and is often associated with antibodies againstRNA polymerase (in 59% of cases). Many proceed to dialysis, although this can be stopped within three years in about a third of cases. Higher age and (paradoxically) a lower blood pressure at presentation make dialysis more likely to be needed.[23]
Treatments for SRC include ACE inhibitors. Prophylactic use of ACE inhibitors is currently not recommended, as recent data suggest a poorer prognosis in patient treated with these drugs prior to the development of renal crisis.[24][unreliable medical source?] Transplanted kidneys are known to be affected by scleroderma, and patients with early-onset renal disease (within one year of the scleroderma diagnosis) are thought to have the highest risk for recurrence.[25]
No clear cause for scleroderma and systemic sclerosis has been identified. Genetic predisposition appears to be limited, as genetic concordance is small; still, a familial predisposition for autoimmune disease is often seen. Polymorphisms inCOL1A2 andTGF-β1 may influence severity and development of the disease. Evidence implicatingcytomegalovirus (CMV) as the original epitope of the immune reaction is limited, as is parvovirus B19.[26]Organic solvents and other chemical agents have been linked with scleroderma.[27]
One of the suspected mechanisms behind the autoimmune phenomenon is the existence ofmicrochimerism, i.e. fetal cells circulating in maternal blood, triggering an immune reaction to what is perceived as foreign material.[27][28]
A distinct form of scleroderma and systemic sclerosis may develop in patients withchronic kidney failure. This form,nephrogenic fibrosing dermopathy or nephrogenic systemic fibrosis,[29][30][31][32] has been linked to exposure togadolinium-containingradiocontrast.[33]
Bleomycin[34] (a chemotherapeutic agent) and possiblytaxane chemotherapy[35] may cause scleroderma, and occupational exposure tosolvents has been linked to an increased risk of systemic sclerosis.[36]
Overproduction of collagen is thought to result from an autoimmune dysfunction, in which the immune system starts to attack thekinetochore of the chromosomes. This would lead to genetic malfunction of nearby genes.T cells accumulate in the skin; these are thought to secretecytokines and other proteins that stimulate collagen deposition. Stimulation of thefibroblast, in particular, seems to be crucial to the disease process, and studies have converged on the potential factors that produce this effect.[27]
A significant player in the process istransforming growth factor (TGFβ). This protein appears to be overproduced, and the fibroblast (possibly in response to other stimuli) also overexpresses the receptor for this mediator. An intracellular pathway (consisting ofSMAD2/SMAD3,SMAD4, and the inhibitorSMAD7) is responsible for the secondary messenger system that inducestranscription of the proteins and enzymes responsible for collagen deposition.Sp1 is atranscription factor most closely studied in this context. Apart from TGFβ,connective tissue growth factor (CTGF) has a possible role.[27] Indeed, a commonCTGF gene polymorphism is present at an increased level in systemic sclerosis.[37]
Damage toendothelium is an early abnormality in the development of scleroderma, and this, too, seems to be due to collagen accumulation by fibroblasts, although direct alterations by cytokines,platelet adhesion, and a type II hypersensitivity reaction similarly have been implicated. Increasedendothelin and decreasedvasodilation have been documented.[27]
Jimenez and Derk[27] describe three theories about the development of scleroderma:
In 1980, theAmerican College of Rheumatology agreed on diagnostic criteria for scleroderma.[38]
Diagnosis is by clinical suspicion, presence of autoantibodies (specificallyanticentromere and anti-scl70/antitopoisomerase antibodies), and occasionally by biopsy. Of the antibodies, 90% have a detectableantinuclear antibody. Anticentromere antibody is more common in the limited form (80–90%) than in the diffuse form (10%), and anti-scl70 is more common in the diffuse form (30–40%) and in African-American patients (who are more susceptible to the systemic form).[27]
Other conditions may mimic systemic sclerosis by causing hardening of the skin. Diagnostic hints that another disorder is responsible include the absence of Raynaud's phenomenon, a lack of abnormalities in the skin on the hands, a lack of internal organ involvement, and a normal antinuclear antibodies test result.[39]
No cure for scleroderma is known, though treatments exist for some of the symptoms, including drugs that soften the skin and reduce inflammation. Some patients may benefit from exposure to heat.[40] Holistic care of patients comprising patient education tailored to patients' education level is useful in view of the complex nature of the disease symptoms and progress.[41]
Topical treatment for the skin changes of scleroderma do not alter the disease course, but may improve pain and ulceration. A range ofnonsteroidal anti-inflammatory drugs, such asnaproxen, can be used to ease painful symptoms.[citation needed] The benefit fromsteroids such as prednisone is limited.[citation needed] Episodes of Raynaud's phenomenon sometimes respond tonifedipine or other calcium channel blockers; severe digital ulceration may respond toprostacyclin analogueiloprost, and the dual endothelin-receptor antagonistbosentan may be beneficial for Raynaud's phenomenon.[42] Skin tightness may be treated systemically withmethotrexate andciclosporin.[42] and the skin thickness can be treated with penicillamine.
Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis that may be the initial manifestation of the disease. Renal vascular injury (due in part to collagen deposition) leads to renal ischemia, which results in activation of the renin-angiotensin-aldosterone system (RAAS). This raises blood pressure and further damages the renal vasculature, causing a vicious cycle of worsening hypertension and renal dysfunction (e.g., elevated creatinine, edema). Hypertensive emergency with end-organ dysfunction (e.g., encephalopathy, retinal hemorrhage) is common. Thrombocytopenia and microangiopathic hemolytic anemia can be seen. Urinalysis is usually normal but may show mild proteinuria, as in this patient; casts are unexpected.[citation needed]
The mainstay of therapy for SRC includes ACE inhibitors, which reduce RAAS activity and improve renal function and blood pressure. Short-acting ACE inhibitors (typically captopril) are used because they can be rapidly uptitrated. An elevated serum creatinine level is not a contraindication for ACE inhibitors in this population, and slight elevations in creatinine are common during drug initiation.
Scleroderma renal crisis, the occurrence ofacute kidney injury, andmalignant hypertension (very high blood pressure with evidence of organ damage) in people with scleroderma are effectively treated with drugs from the class of the ACE inhibitors. The benefit of ACE inhibitors extends even to those who have to commencedialysis to treat their kidney disease, and may give sufficient benefit to allow the discontinuation of renal replacement therapy.[42]
Active alveolitis is often treated with pulses ofcyclophosphamide, often together with a small dose of steroids. The benefit of this intervention is modest.[43][44]
Pulmonary hypertension may be treated withepoprostenol,treprostinil,bosentan, and possibly aerolized iloprost.[42]Nintedanib was approved for use in the United StatesFood and Drug Administration on September 6, 2019, to slow the rate of decline in pulmonary function in patients with systemic sclerosis-associatedinterstitial lung disease (SSc-ILD).[45][46]
Some evidence indicates thatplasmapheresis (therapeutic plasma exchange) can be used to treat the systemic form of scleroderma. In Italy, it is a government-approved treatment option. This is done by replacingblood plasma with a fluid consisting ofalbumin, and is thought to keep the disease at bay by reducing the circulation of scleroderma autoantibodies.[47]
Systemic scleroderma is arare disease, with an annual incidence that varies in different populations. Estimates of incidence (new cases per million people) range from 3.7 to 43 in the United Kingdom and Europe, 7.2 in Japan, 10.9 in Taiwan, 12.0 to 22.8 in Australia, 13.9 to 21.0 in the United States, and 21.2 in Buenos Aires.[48] The interval of peak onset starts at age 30[49] and ends at age 50.[49]
Globally, estimates of prevalence vary from 31.0 to 658.6 affected people per million.[48] Systemic sclerosis has a female:male ratio of 3:1 (8:1 in mid- to late childbearing years). Incidence is twice as high among African Americans. Full-bloodedChoctaw Native Americans in Oklahoma have the highest prevalence in the world (469 per 100,000).[50]
The disease has some hereditary association. It may also be caused by an immune reaction to a virus (molecular mimicry) or by toxins.[2]
The Juvenile Scleroderma Network is an organization dedicated to providing emotional support and educational information to parents and their children living with juvenile scleroderma, supporting pediatric research to identify the cause of and the cure for juvenile scleroderma, and enhancing public awareness.[51]
In the US, the Scleroderma Foundation is dedicated to raise awareness of the disease and assist those who are affected.[52]
TheScleroderma Research Foundation sponsors research into the condition.[53] Comedian and television presenterBob Saget, a board member of the SRF, directed the 1996 ABC TV movieFor Hope, starringDana Delany, which depicts a young woman fatally affected by scleroderma; the film was based on the experiences of Saget's sister Gay.[54]
Scleroderma and Raynaud's UK is a British charity formed by the merger of two smaller organisations in 2016 to provide support for people with scleroderma and fund research into the condition.[55][56]
A 2018 study placed 10-year survival rates at 88%, without differentiation based on subtype. Diffuse systemic sclerosis, internal organ complications, and older age at diagnosis are associated with worse prognoses.[57]
Given the difficulty in treating scleroderma, treatments with a smallerevidence base are often tried to control the disease. These includeantithymocyte globulin andmycophenolate mofetil; some reports have shown improvements in the skin symptoms, as well as delaying the progress of systemic disease, but neither has been subjected to large clinical trials.[42]
Autologoushematopoietic stem cell transplantation (HSCT) is based on the assumption that autoimmune diseases such as systemic sclerosis occur when the white blood cells of the immune system attack the body. In this treatment, stem cells from the patient's blood are extracted and stored to preserve them. The patient's white blood cells are destroyed with cyclophosphamide and rabbit antibodies against the white blood cells. Then, the stored blood is returned to the patient's bloodstream to reconstitute a healthy blood and immune system that will not attack the body. The results of a phase-III trial, the Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, with 156 patients, were published in 2014. HSCT itself has a high treatment mortality, so in the first year, the survival of patients in the treatment group was lower than the placebo group, but at the end of 10 years, the survival in the treatment group was significantly higher. The authors concluded that HSCT could be effective, if limited to patients who were healthy enough to survive HSCT itself. Therefore, HSCT should be given early in the progression of the disease, before it does damage. Patients with heart disease, and patients who smoked cigarettes, were less likely to survive.[58][59] Another trial, the Stem Cell Transplant vs. Cyclophosphamide (SCOT) trial, is ongoing.[60]
Asengeprast is an experimental systemic scleroderma drug candidate. It is a small molecule inhibitor of the G-protein coupled receptor GPR68 with antifibrotic activity.
