Systemic Sclerosis
Systemic sclerosis (SSc) is a chronic, multisystem, heterogeneous autoimmune disease. Individuals with SSc have a mortality rate approximately 2.8 times that of the general population. In the United States, the incidence is approximately 15 cases per 100,000 person-years.
The disease is characterized by inflammation, vasculopathy, and progressive fibrosis of the skin and internal organs.
SSc is frequently referred to as scleroderma; however, scleroderma includes SSc and localized forms of scleroderma that affect only the skin.
The 2 main types of SSc are defined according to the pattern of skin involvement:
limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc).
In lcSSc, skin thickening is present distal to the elbows and knees, and facial skin thickening may or may not be present.
In contrast, dcSSc is characterized by thickening of the skin of the whole extremity, as well as that of the anterior chest, abdomen, and back, with or without facial skin involvement.
Multiple organs, including the heart, lungs, gastrointestinal tract, and kidneys, can be affected in both forms, though organ involvement is generally less severe in lcSSc.
CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) occurs frequently in lcSSC but can also occur in longstanding dcSSc.
Of patients with SSc, approximately 55% have lcSSc and 35% have dcSSc. The remaining 10% of patients with SSc have sine scleroderma or an overlap syndrome.
Sine scleroderma is a form of SSc that has characteristic clinical features but spares the skin. Overlap syndromes occur when features of another autoimmune disease are present along with SSc.
Early treatment of SSc can improve outcomes, so prompt diagnosis is important. However, diagnosis can be challenging because many patients present with nonspecific symptoms such as Raynaud phenomenon, gastroesophageal reflux, puffy fingers, and fatigue.
In addition, patients with other autoimmune disorders may present with symptoms suggestive of SSc. Testing for autoantibodies that are associated with SSc assists diagnosis and can help predict organ involvement and severity of disease.
References:
Lee YH. Overall and sex- and disease subtype-specific mortality in patients with systemic sclerosis: an updated meta-analysis. Z Rheumatol. 2019;78(2):195-201. doi:10.1007/s00393-018-0492-8
Fan Y, Bender S, Shi W, et al. Incidence and prevalence of systemic sclerosis and systemic sclerosis with interstitial lung disease in the United States. J Manag Care Spec Pharm. 2020;26(12):1539-1547. doi:10.18553/jmcp.2020.20136
Lee JJ, Pope JE. Diagnosis and management of systemic sclerosis: a practical approach. Drugs. 2016;76(2):203-213. doi:10.1007/s40265-015-0491-x
Young A, Khanna D. Systemic sclerosis: commonly asked questions by rheumatologists. J Clin Rheumatol. 2015;21(3):149-155. doi:10.1097/RHU.0000000000000232
Denton CP, Khanna D. Systemic sclerosis. Lancet. 2017;390(10103):1685-1699. doi:10.1016/s0140-6736(17)30933-9
CENP-A
Optimal range: 0 - 11 SI
CENP-A stands for centromere proteins A.
Centromere antibodies can be directed against a number of centromere proteins (CENP), including CENP-A, -B, and -C, though CENP-B is thought to be the main target.
These antibodies are found in 20% to 40% of patients with SSc and are associated with the lcSSc subtype.
Furthermore, centromere antibodies are included in the 2013 ACR-EULAR classification criteria. However, these antibodies can occur in other connective tissue diseases, including:
- systemic lupus erythematosus (SLE),
- primary biliary cholangitis,
- rheumatoid arthritis,
- and Sjögren syndrome.
LEARN MORECENP-B
Optimal range: 0 - 11 SI
CENP-B stands for centromere proteins B.
Centromere antibodies can be directed against a number of centromere proteins (CENP), including CENP-A, -B, and -C, though CENP-B is thought to be the main target.
These antibodies are found in 20% to 40% of patients with SSc and are associated with the lcSSc subtype.
Furthermore, centromere antibodies are included in the 2013 ACR-EULAR classification criteria. However, these antibodies can occur in other connective tissue diseases, including:
- systemic lupus erythematosus (SLE),
- primary biliary cholangitis,
- rheumatoid arthritis,
- and Sjögren syndrome.
LEARN MOREFibrillarin
Optimal range: 0 - 11 SI
U3-RNP antibodies target the U3 small nucleolar ribonucleoprotein (U3-RNP) complex, which consists of the protein fibrillarin and U3 RNA. These antibodies are found in about 4% to 10% of patients with SSc, and are especially common in African American SSc patients (approximately 30%). U3-RNP antibodies are rarely found in patients with other autoimmune disorders; thus, the presence of these antibodies supports a SSc diagnosis.
These antibodies occur most often in dcSSc, but they can also occur in lcSSc.
U3-RNP antibodies are associated with multiorgan involvement, including the heart, kidneys, muscle, lungs, and gastrointestinal system. Their presence is an independent risk factor for the development of PAH, and PAH is the most common cause of death in U3-RNP–positive patients. Therefore, their presence indicates a poorer prognosis.
LEARN MOREPM/Scl-100
Optimal range: 0 - 11 SI
PM/Scl antibodies target the PM/Scl exosome complex, and most reactivity is against 2 proteins, PM/Scl-75 and PM/Scl-100. They are present in 2% to 11% of SSc patients and are associated with SSc-myositis overlap syndrome and lcSSc. PM/Scl antibodies also occur in other autoimmune diseases such as polymyositis and dermatomyositis.
The presence of either PM/Scl-75 or PM/Scl-100 antibody is associated with calcinosis, and the co-occurrence of both antibodies is associated with inflammatory myositis.
However, each antibody may be associated with a distinct clinical phenotype; gastrointestinal symptoms and ILD are common in patients with PM/Scl-75 antibodies but less so in those with PM/Scl-100 antibodies. Internal organ involvement generally remains mild in patients with any PM/Scl antibodies, and the presence of these antibodies is associated with an overall favorable prognosis.
LEARN MOREPM/Scl-75
Optimal range: 0 - 11 SI
PM/Scl antibodies target the PM/Scl exosome complex, and most reactivity is against 2 proteins, PM/Scl-75 and PM/Scl-100. They are present in 2% to 11% of SSc patients and are associated with SSc-myositis overlap syndrome and lcSSc. PM/Scl antibodies also occur in other autoimmune diseases such as polymyositis and dermatomyositis.
The presence of either PM/Scl-75 or PM/Scl-100 antibody is associated with calcinosis, and the co-occurrence of both antibodies is associated with inflammatory myositis.
However, each antibody may be associated with a distinct clinical phenotype; gastrointestinal symptoms and ILD are common in patients with PM/Scl-75 antibodies but less so in those with PM/Scl-100 antibodies. Internal organ involvement generally remains mild in patients with any PM/Scl antibodies, and the presence of these antibodies is associated with an overall favorable prognosis.
LEARN MORERP11
Optimal range: 0 - 11 SI
RNA polymerase III antibodies target RNA polymerase epitopes 11 and 155 and are thus also known as anti-RP11 and anti-RP155.
These antibodies are found in 7% to 41% of patients with SSc and occur most often in dcSSc.
They are diagnostic for SSc, as they are rarely found in other autoimmune diseases, and are included in the 2013 ACR-EULAR classification criteria.
The presence of RNA polymerase III antibodies is associated with progressive skin thickening, gastric antral vascular ectasia (GAVE), and renal crisis.
In addition, these antibodies are associated with onset of cancer within a 2-year timeframe before or after onset of SSc skin changes. Historically, RNA polymerase III antibodies indicated a poor prognosis, but mortality rates improved after the introduction of ACE inhibitors to treat renal crisis; the prognosis for patients with RNA polymerase III antibodies is now better than for those with Scl-70 or U3-RNP antibodies.
LEARN MORERP155
Optimal range: 0 - 11 SI
RNA polymerase III antibodies target RNA polymerase epitopes 11 and 155 and are thus also known as anti-RP11 and anti-RP155.
These antibodies are found in 7% to 41% of patients with SSc and occur most often in dcSSc.
They are diagnostic for SSc, as they are rarely found in other autoimmune diseases, and are included in the 2013 ACR-EULAR classification criteria.
The presence of RNA polymerase III antibodies is associated with progressive skin thickening, gastric antral vascular ectasia (GAVE), and renal crisis.
In addition, these antibodies are associated with onset of cancer within a 2-year timeframe before or after onset of SSc skin changes. Historically, RNA polymerase III antibodies indicated a poor prognosis, but mortality rates improved after the introduction of ACE inhibitors to treat renal crisis; the prognosis for patients with RNA polymerase III antibodies is now better than for those with Scl-70 or U3-RNP antibodies.
LEARN MOREScl-70
Optimal range: 0 - 11 SI
Scl-70 is also known as Topoisomerase I Antibody.
Topoisomerase I antibodies were initially named Scl-70 based on immunoblot detection of a 70-kDa protein.
The prevalence of Scl-70 antibodies in SSc varies widely across geographies and ethnicities, ranging from 9% to 71%.
These antibodies are strongly associated with dcSSc but also occur in lcSSc.
The 2 main types of SSc are defined according to the pattern of skin involvement: limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc). In lcSSc, skin thickening is present distal to the elbows and knees, and facial skin thickening may or may not be present. In contrast, dcSSc is characterized by thickening of the skin of the whole extremity, as well as that of the anterior chest, abdomen, and back, with or without facial skin involvement. Multiple organs, including the heart, lungs, gastrointestinal tract, and kidneys, can be affected in both forms, though organ involvement is generally less severe in lcSSc. CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) occurs frequently in lcSSc but can also occur in longstanding dcSSc.
LEARN MORETh/To
Optimal range: 0 - 11 SI
Th/To antibodies target RNase P and mitochondrial RNase ribonucleoprotein complexes. These antibodies are found in 2% to 5% of SSc patients and are primarily associated with lcSSc. Th/To antibodies are rarely found in other autoimmune diseases but can occur in patients with localized scleroderma.
Patients with Th/To antibodies often develop both ILD and PAH and thus have a poorer prognosis than other patients with lcSSc.
LEARN MOREU1-snRNP RNP A
Optimal range: 0 - 11 SI
U1-snRNP antibodies, also referred to as U1-RNP and Smith (Sm)/RNP, target 3 components of the U1 small nuclear ribonucleoprotein complex: U1-snRNP RNP A, U1-snRNP RNP C, and U1-snRNP RNP-70kd.
These antibodies, found in 2% to 14% of SSc patients, are more frequent in lcSSc than in dcSSc.
The 2 main types of SSc are defined according to the pattern of skin involvement: limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc).
In lcSSc, skin thickening is present distal to the elbows and knees, and facial skin thickening may or may not be present. In contrast, dcSSc is characterized by thickening of the skin of the whole extremity, as well as that of the anterior chest, abdomen, and back, with or without facial skin involvement. Multiple organs, including the heart, lungs, gastrointestinal tract, and kidneys, can be affected in both forms, though organ involvement is generally less severe in lcSSc.
CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) occurs frequently in lcSSC but can also occur in longstanding dcSSc.
The antibodies are also found in patients with other autoimmune diseases, including approximately 90% of patients with mixed connective tissue disease.
LEARN MOREU1-snRNP RNP C
Optimal range: 0 - 11 SI
U1-snRNP antibodies, also referred to as U1-RNP and Smith (Sm)/RNP, target 3 components of the U1 small nuclear ribonucleoprotein complex: U1-snRNP RNP A, U1-snRNP RNP C, and U1-snRNP RNP-70kd.
These antibodies, found in 2% to 14% of SSc patients, are more frequent in lcSSc than in dcSSc.
The 2 main types of SSc are defined according to the pattern of skin involvement: limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc).
In lcSSc, skin thickening is present distal to the elbows and knees, and facial skin thickening may or may not be present. In contrast, dcSSc is characterized by thickening of the skin of the whole extremity, as well as that of the anterior chest, abdomen, and back, with or without facial skin involvement. Multiple organs, including the heart, lungs, gastrointestinal tract, and kidneys, can be affected in both forms, though organ involvement is generally less severe in lcSSc.
CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) occurs frequently in lcSSC but can also occur in longstanding dcSSc.
The antibodies are also found in patients with other autoimmune diseases, including approximately 90% of patients with mixed connective tissue disease.
LEARN MOREU1-snRNP RNP-70kd
Optimal range: 0 - 11 SI
U1-snRNP antibodies, also referred to as U1-RNP and Smith (Sm)/RNP, target 3 components of the U1 small nuclear ribonucleoprotein complex: U1-snRNP RNP A, U1-snRNP RNP C, and U1-snRNP RNP-70kd.
These antibodies, found in 2% to 14% of SSc patients, are more frequent in lcSSc than in dcSSc.
The 2 main types of SSc are defined according to the pattern of skin involvement: limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc).
In lcSSc, skin thickening is present distal to the elbows and knees, and facial skin thickening may or may not be present. In contrast, dcSSc is characterized by thickening of the skin of the whole extremity, as well as that of the anterior chest, abdomen, and back, with or without facial skin involvement. Multiple organs, including the heart, lungs, gastrointestinal tract, and kidneys, can be affected in both forms, though organ involvement is generally less severe in lcSSc.
CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) occurs frequently in lcSSC but can also occur in longstanding dcSSc.
The antibodies are also found in patients with other autoimmune diseases, including approximately 90% of patients with mixed connective tissue disease.
LEARN MORE