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Keywords:

  • antinuclear antibodies;
  • clinical features;
  • prognosis;
  • systemic sclerosis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Acknowledgments
  5. References

Systemic sclerosis (SSc) is thought to be an autoimmune disease, as autoantibodies against a variety of extractable nuclear antigens can be detected in patient sera. Subgrouping patients based on the type of autoantibodies present can be useful in diagnosis and management. Anti-centromere antibodies (ACA) and anti-topoisomerase I antibodies (anti-topo I) are the classic autoantibodies associated with SSc. ACA are associated with limited cutaneous involvement and isolated pulmonary hypertension, whereas anti-topo I are associated with diffuse skin involvement and pulmonary fibrosis. ACA are predictors for a favorable prognosis, while anti-topo I are correlated with a poor prognosis and SSc-related mortality. Additionally, anti-RNA polymerase antibodies (anti-RNAP) are associated with diffuse cutaneous disease and renal involvement. Anti-nucleolar antibodies define multiple subgroups of patients with SSc. Of these, anti-Th/To antibodies (anti-Th/To) and anti-PM-Scl antibodies (anti-PM-Scl) are associated with limited cutaneous SSc (lSSc), whereas anti-U3RNP antibodies (anti-U3RNP) are associated with diffuse cutaneous SSc (dSSc). In addition, anti-Th/To and anti-U3RNP can be predictors for a less favorable prognosis with a higher frequency of organ involvement, such as pulmonary fibrosis, pulmonary hypertension and renal crisis. Other autoantibodies are less frequently reported: anti-Ku antibodies, anti-U1RNP antibodies, anti-human upstream-binding factor, and anti-U11/U12 antibodies. These antibodies are generally less specific to SSc, but also define clinically distinct patient subsets. Thus, characterization of autoantibodies in SSc together with knowledge of disease characteristics intrinsic to distinct patient populations is helpful for assessing the clinical presentation and prognosis of this disease, and for monitoring patients with SSc.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Acknowledgments
  5. References

Systemic sclerosis (SSc) is a connective tissue disorder characterized by microvascular damage and excessive fibrosis of the skin and various internal organs. It is well known that the clinical manifestations of SSc vary, from limited cutaneous SSc (lSSc), in which skin thickening is relatively restricted to the fingers and hands with less serious internal organ involvement, to diffuse cutaneous SSc (dSSc), in which skin lesions are extensive and often rapidly developing with earlier and more serious complications.1 In addition, autoantibodies against a variety of self antigens have been detected in SSc patients, and their presence may be related to disease course and progression.

One representative feature of the immunological abnormalities in SSc patients is the presence of antinuclear antibodies (ANA). ANA are present in more than 90% of SSc patients, and these ANA react against various intracellular components.2 However, production of specific ANA is exclusive, in that one patient rarely has two or more types of SSc-related ANA.3 Once a particular specificity of ANA are present, this usually remains throughout the course of disease, and other ANA specificities typically do not arise.4 Although a definitive role for ANA in the pathogenesis in SSc has not been shown, the particular ANA types are often indicative of clinical features, disease course and overall severity. Therefore, information regarding ANA is a valuable tool to aid in the diagnosis and evaluation of prognosis of an individual SSc patient.

Anti-centromere antibodies (ACA) and anti-topoisomerase I antibodies (anti-topo I, formerly anti-Scl-70) are the classic ANA found in SSc. In addition to these ANA, anti-nucleolar antibodies (ANoA) are found less frequently in SSc patients and comprise clinically distinct subsets. They produce nucleolar staining patterns by indirect immunofluorescence staining (IIF) on human epithelioma type 2 (HEp-2) cells. ANoA are directed against different nucleolar proteins such as RNA polymerase (RNAP), small nuclear ribonucleoproteins (snRNP, Th/To) and fibrillarin components (U3RNP).5 Among them, anti-RNAP antibodies (anti-RNAP) frequently do not produce nucleolar staining with IIF but instead yield a speckled nucleolar pattern. They are intrinsically specific to SSc and are rarely found in other diseases or in healthy individuals.6

Screening for ANA is usually performed through IIF using HEp-2 cells. This technique is recommended as the first ANA screening method as it is highly sensitive.7 Representative staining patterns are shown in Figure 1. Except for ACA, it is difficult to identify the specific ANA by IIF because epitopes cannot be well-defined using this technique. Therefore, additional techniques such as enzyme-linked immunosorbent assay (ELISA), immunodiffusion and immunoprecipitation (Fig. 2) are required to confirm ANA in a patient’s sera (Table 1). There currently remains a need for standardization of ANA determination although evidence-based guidelines for the use of specific immunoassays in SSc have recently been suggested.8

image

Figure 1.  Indirect immunofluorescence pattern on HEp-2 cells stained with anti-centromere antibody (Ab) (a), anti-Th/To Ab (b), and anti-U3RNP Ab (c) serum (original magnification ×400). Anti-centromere antibody shows a homogeneously distributed and speckled pattern in the nucleus. This pattern is termed “discrete-speckled”. Anti-Th/To antibody shows dotty nucleolar staining of interphase cells and the mitotic chromosome is not stained. Anti-U3RNP antibody demonstrates clumpy nucleolar staining of interphase cells and the mitotic chromosome is stained.

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image

Figure 2.  Immunoprecipitation assay of autoantibodies related to systemic sclerosis. (a) Immunoprecipitation of U1RNP, Th/To and U3RNP by sera. K562 cell extracts were immunoprecipitated with sera and RNA was extracted, run on an 8% urea–polyacrylamide gel, followed by silver staining. Total RNA, with the 7.0, 5.8 and 5.0 S small ribosomal RNA and the tRNA region indicated: lane 1, anti-U1RNP-positive sera; lane 2, anti-Th/To-positive sera; lane 3, anti-U3RNP-positive sera; lane 4, normal human serum (NHS). (b), Immunoprecipitation of 35S-methionine-labeled K562 cell extracts was performed using sera from patients with SSc (lane 1–5) and NHS, separated on 10% sodium dodecylsulfate polyacrylamide gel electrophoresis and analyzed by autoradiography. Topoisomerase-I (topo-I, lane 1), U1RNP (lane 2), RNA polymerase I/III and II (RNAP I/III and II, lane 3), Th/To (lane 4) and U3RNP (lane 5) proteins are shown by arrowheads or indicated region.

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Table 1.   Autoantibodies to nuclear autoantigens in systemic sclerosis
AntibodyMajor autoantigenCellular localizationIIFAssay
  1. IIF, indirect immunofluorescence staining pattern on HEp-2 cells; ELISA, enzyme-linked immunosorbent assay; WB, western blotting; DID, double immunodiffusion; IP, immunoprecipitation; RNAP, RNA polymerase.

Anti-centromereCENP-A, B and CChromatinDiscrete-speckledIIF, ELISA, WB
Anti-topoisomerase IDNA topoisomerase IChromatinHomogenous and nucleolarDID, ELISA, IP, WB
Anti-RNAPRNA polymeraseNucleoli, nucleoplasmSpeckled and/or nucleolarELISA, IP
Anti-Th/ToH1/8-2 and Th/7-2 RNA, components of RNase P and RNase MRPNucleoliNucleolarIP
Anti-U3RNPFibrillarin and other U3RNP componentsNucleoliNucleolarIP
Anti-hUBF (NOR90)Human upstream binding factorNucleoliNucleolarIP
Anti-U1RNP70 kDa, A and C polypeptides of U1 snRNPNucleoplasmSpeckledDID, ELISA, IP, WB
Anti-PM-SclC1D, PM-Scl-100 and PM-Scl-75 proteins of the human exosomeNucleoliNucleolarDID, IP
Anti-Ku80 and 70 kDa DNA binding dimeric proteinNucleoplasmSpeckledDID, IP

Of particular importance is the observation that a patient’s genetic background affects the prevalence and clinical features of SSc, even when the same ANA specificities are present in sera. For instance, anti-PM-Scl antibodies (anti-PM-Scl) are detected in approximately 4% of white/African-American patients, but not in Japanese SSc patients.9,10 Pulmonary hypertension is often seen in ACA-positive white and African-American SSc patients and causes an increased mortality in this subgroup, but this complication is relatively rare in Japanese SSc patients.9–11 Therefore, genetic differences should be taken into account when considering the association of ANA with clinical features and prognosis in SSc.

This review focuses both on important classical and recently discovered autoantibodies in SSc and their relevance to disease course and progression. Although some are established markers of the disease, I discuss recent evidence for their roles as predictors for specific organ involvement, prognosis and pathogenesis.

Antinuclear antibodies in SSc

Anti-centromere antibodies

ACA were described by Moroi et al. in 1980.12 In IIF, they produce punctate spots dispersed in the interphase nucleus, localized to the constriction on metaphase chromosomes. A typical ACA staining pattern on HEp-2 cells is shown in Figure 1(a). At least six centromeric polypeptides, CENP-A to F, have been defined. CENP-B, which is an 80-kDa haploid DNA-binding protein, is the major autoantigen reacting to virtually all ACA-positive sera13,14 (Table 1). For clinical use, a solid-phase ELISA system using a cloned fusion protein of the CENP-B antigen has been established with adequate sensitivity and specificity.15,16

Although the frequency of ACA in patients with SSc has been reported to be 20–30% overall, it varies among different ethnic populations. Approximately 30% of white SSc patients are positive for ACA, whereas the frequency is lower in African-American and Thai patients with SSc.17,18 ACA are rarely found in healthy individuals or in patients with other connective tissue diseases, although ACA are also associated with primary biliary cirrhosis.19,20 When ACA are found in patients with Raynaud’s phenomenon, this is predictive for the future development of lSSc.21 It is reported that the genetic factors are associated with ANA specificities. ACA are immunogenetically associated with human leukocyte antigen (HLA) molecules DR1, DR4, DR8, DR11 and DQ7 (DQB1*0301).22,23 Strong non-HLA genetic markers have recently been reported in tumor necrosis factor (TNF) polymorphisms, such as the TNF-863A and TNF-1031C alleles.24 This indicates that the immunogenetic background contributes to the autoantibody response or clinical subtype of SSc.18,24

Anti-centromere antibodies in SSc patients are associated with limited skin involvement, peripheral vascular damage and calcinosis (Table 2).25 Although almost all ACA-positive patients suffer from Raynaud’s phenomenon, the degree of ischemia varies depending on ethnicity. While frequencies of pitting scars or ulcers were 42–61% in white and/or African American patients,9,26,27 these complications arose in only 11–17% in Japanese patients with ACA.10,11 The presence of ACA are predictive for development of pulmonary hypertension but not pulmonary fibrosis.7,28 It has been reported that ACA titers measured by ELISA are generally stable over time in individual patients, and titers are not associated with disease activity.29,30 ACA-positive SSc patients possess a more favorable prognosis than patients with other SSc-related ANA.28 Two recent large cohort studies have also reported that SSc patients with ACA had a lower mortality than those with anti-topo I or ANoA.27,31

Table 2.   Predominant clinical features associated with major systemic sclerosis-related antinuclear antibodies
 Disease subsetOrgan involvement
  1. RNAP, RNA polymerase; SSc, systemic sclerosis.

Anti-centromereDiffuseDigital ulcers and gangrene, calcinosis Isolated pulmonary arterial hypertension
Anti-topoisomerase ILimitedDigital ulcers and gangrene Pulmonary fibrosis Severe heart disease Renal crisis
Anti-RNAPDiffuseRenal crisis
Anti-Th/ToLimitedIsolated pulmonary arterial hypertension Pulmonary fibrosis
Anti-U3RNPDiffuseIsolated pulmonary arterial hypertension Pulmonary fibrosis Severe heart disease Myositis
Anti-U1RNPLimitedIsolated pulmonary arterial hypertension Joint inflammation SSc–myositis overlap
Anti-PM-SclLimitedSSc–myositis overlap
Anti-topoisomerase I antibodies

Autoantibodies against a chromatin-associated protein of 70–100 kDa were first described in patients with SSc in 1979.32 Later, this protein was identified as topoisomerase I33 (Table 1). Anti-topo I were found in approximately 40% of patients with SSc overall, but ethnic differences considerably affect prevalence, which ranges 28–70%.8,10 For example, the prevalence of anti-topo I is low in white patients but higher in Japanese and Thai. Anti-topo I are associated with HLA-DRB1, DQB1 and DPB1.18,23,34,35 Among them, DRB1*11 is associated with anti-topo I in all ethnic groups, with HLA-DRB1*1101 found in whites and African-Americans, HLA-DRB1*1104 found in Japanese, and HLA-DRB1*1502 found in whites and Hispanics. Anti-topo I are not usually found in healthy individuals, in patients with other connective diseases or primary Raynaud’s syndrome.8 Coexistence with ACA is rare and only occurs in approximately 0.5% of SSc patients.36,37 Anti-topo I are detected in approximately 40% of patients with dSSc, but less than 10% of patients with lSSc.8,38 In another report, approximately one-third of anti-topo I-positive patients had lSSc.39 Furthermore, anti-topo I are associated with a higher risk for severe pulmonary fibrosis early in disease (Table 2). Additionally, anti-topo I may be a predictor for the development of renal crisis.39 SSc patients with anti-topo I have been reported to have a higher risk for internal malignancies,40–43 yet this trend is not always observed,44 and the association between anti-topo I and malignancy risk remains controversial.

It is generally believed that serial measurement of autoantibody titers is not useful for assessment of disease severity and activity. However, several recent studies have demonstrated that anti-topo I levels determined by ELISA were associated with extent of disease severity, including skin thickness, and that seronegative conversion resulted in disease remission.45–48 Previously, it had been reported that patients with anti-RNAP had the lowest survival rate.9 However, mortality rates in patients with anti-RNAP are currently better than those with anti-topo I, and therefore anti-topo I are now considered to be a marker for poor prognosis. This increased survival rate is due to the fact that patients with anti-RNAP have a low risk of suffering pulmonary fibrosis, and in addition renal crisis is now more readily treated with angiotensin-converting enzyme (ACE) inhibitors.49

Recently, in vitro studies have revealed direct pathogenic effects of the autoantibodies found in SSc. Henault et al.50 have reported that the autoantigen topo I was bound specifically to fibroblasts, where it was recognized by anti-topo I from SSc patients. The binding of anti-topo I subsequently stimulated adhesion and activation of cultured monocytes. Topo I released from apoptotic endothelial cells also bound specifically to fibroblasts. Thus, it is possible that, in vivo, topo I binds to fibroblast surfaces, recruits anti-topo I and subsequently induces monocyte adhesion and activation, leading to the development of SSc.

Anti-RNA polymerase I, II and III antibodies

A subset of SSc patients possess autoantibodies against one or more subtypes of RNAP.4,51,52 Autoantibodies to RNAP I and RNAP III (anti-RNAP I and III) routinely coexist, and this pattern is highly specific for SSc (Table 1).4,51,52 Some patients who are positive for anti-RNAP I and III also have anti-RNAP II antibodies (anti-RNAP II). Autoantibodies to RNAP II alone are rare and display a nucleolar staining pattern by IIF, but are not specific for SSc because they are detected in systemic lupus erythematosus (SLE) and overlap syndrome.53 The HLA associations of anti-RNAP in patients remains controversial.3,54

Co-production of anti-RNAP I and III is specific to SSc with a prevalence of approximately 20%.55 The presence of both anti-RNAP I and III, with or without anti-RNAP II, is associated with diffuse cutaneous involvement and higher risk for renal crisis (Table 2).8,51,52,56 A recent study confirmed a high prevalence of renal crisis in 25% of patients with anti-RNAP in contrast to 12% in other patients with dSSc.9 In contrast, pulmonary fibrosis infrequently occurred in this subgroup. Despite the prevalence of renal involvement, the survival rate in patients with anti-RNAP is better than in those with anti-topo I or anti-U3RNP.9 This can be explained by the fact that, although diffuse skin involvement was seen in these patients, a low prevalence of pulmonary fibrosis in combination with early treatment of renal crisis with ACE inhibitors results in improved survival.9

Anti-Th/To antibodies (anti-Th/To, known as anti-7-2RNA antibodies)

Autoantibodies to Th/To were initially reported to be specific for SSc or Raynaud’s disease with a short disease duration,57 but were recently detected in patients with localized scleroderma.58 Anti-Th/To produce a nucleolar, dotty staining pattern in IIF (Fig. 1b) and they immunoprecipitate RNP associated with H1/8-2 and Th/7-2 RNA, which are components of the RNA processing enzymes RNase P and RNase MRP, respectively (Table 1).59,60 Anti-Th/To are linked to HLA DRB1*11.61

Anti-Th/To are present in a small subset of patients with SSc (2–5%) and are associated with limited skin involvement, but a high risk for severe organ involvement and therefore a worse overall prognosis (Table 2).55,62 For example, severe pulmonary fibrosis preceding pulmonary hypertension, as well as renal crisis without interstitial lung disease, have been reported.62,63 However, severe internal organ involvement, with the exception of esophageal dysfunction, is infrequently seen in Japanese patients with anti-Th/To.10,11

Anti-U3RNP antibodies (anti-U3RNP)

Anti-U3RNP antibodies were first found in sera from SSc patients in 1985.5 The major autoantigen of anti-U3RNP is fibrillarin, which is a 34-kDa basic protein and a component of the nucleolar U3-ribonucleoprotein complex (Fig. 2, Table 1). Anti-U3RNP yield a nucleolar, clumpy staining pattern in IIF (Fig. 1c).64 It was reported that anti-U3RNP are associated with HLA DQB1*0604,65 but other reports did not confirm this association.54

Anti-U3RNP are found in 4–10% of patients with SSc.9,64,66 They are generally considered to be specific to SSc and are mutually exclusive with ACA, anti-topo I and anti-RNAP, however, anti-U3RNP have also been described in patients with SLE.7,63 They are more frequently found in African-American patients than in white/Asian SSc patients.9–11,65 Some clinical characteristics are influenced by ethnicity (Table 2). White, African-American and Japanese patients with anti-U3RNP generally have diffuse cutaneous involvement and peripheral vasculopathy, including pitting ulcers and digital gangrene, which are frequently seen in dSSc. In contrast, internal organ involvement characterized by pulmonary fibrosis, pulmonary hypertension and renal crisis is more frequent in whites and African-Americans and therefore these patients have a poor prognosis.9–11,64

Anti-human upstream binding factor (anti-hUBF, formerly anti-NOR 90)

Autoantibodies against nucleolus-organizing region (NOR) 90 were initially described in 1987.67 Subsequent analysis revealed that the autoantigen of anti-NOR 90 antibodies is hUBF (Table 1).68 Anti-hUBF antibodies (anti-hUBF) are not specific to SSc but are found in other connective tissue diseases such as Raynaud’s disease, rheumatoid arthritis, SLE and Sjögren’s syndrome, and also in malignancies.69–71 Anti-hUBF are linked to the HLA-DR1 allele.72 Although large cohort studies have not been performed, a review of accumulated case reports suggests that anti-hUBF are probably associated with limited cutaneous involvement, mild internal organ involvement and a favorable prognosis.70

Anti-U11/U12RNP antibodies (anti-U11/U12RNP)

U11/U12RNP are found in low abundance in eukaryotic cells and components of the spliceosome.73 Fertig et al.74 reported clinical features of 33 SSc patients with anti-U11/U12RNP. All patients with anti-U11/U12RNP had Raynaud’s phenomenon and 82% had gastrointestinal involvement. Although none had intrinsic pulmonary hypertension, a vast majority, 79% of anti-U11/U12RNP positive patients, suffered from pulmonary fibrosis.

Antinuclear antibodies in SSc–myositis overlap

Anti-U1RNP antibodies (anti-U1RNP)

Anti-U1RNP bind to RNP, a ribonuclease-sensitive antigen involved in splicing heterogeneous nuclear RNA into mRNA (Table 1). Anti-U1RNP are widely found in patients with autoimmune connective tissue diseases, particularly those with mixed connective tissue disease, at a high rate of approximately 90% prevalence. In contrast, the prevalence of anti-U1RNP in SSc is approximately 6% (range 2–14%).8–11,75 Patients with anti-U1RNP have less skin thickness and renal involvement, although there is a risk for pulmonary hypertension (Table 2). Puffy hands, Raynaud’s phenomenon, arthritis and esophageal dysfunction are characteristic clinical features in this group. The presence of anti-U1RNP is generally predictive for a favorable response to corticosteroids, resulting in a better prognosis.9,76

Anti-RM-Scl (anti-PM-Scl)

Anti-PM-Scl were first found in patients with polymyositis/scleroderma overlap syndrome (PM/SSc) in 1977.77 The PM-Scl antigen consists of between 11 and 16 polypeptides of which two proteins of 75 and 100 kDa have been identified as the major antigenic components (Table 1).78 IIF staining with anti-PM-Scl yields a homogenous nucleolar pattern. Anti-PM-Scl are strongly associated with HLA DQA1*0501 and HLA DRB1*0301.23 Anti-PM-Scl are found in 4–11% of SSc patients overall. They are found in approximately 25% of scleroderma patients with myositis overlap but in 2% of patients with scleroderma only (Table 2).8,55,79 The frequency of anti-PM-Scl production varies with different ethnicities, for example, large studies of Japanese patients with SSc showed this group to be anti-PM-Scl negative.10,11 Anti-PM-Scl predict for lSSc with no serious internal organ involvement and a good response to low or moderate doses of corticosteroids leading to a favorable prognosis.80

Anti-Ku antibodies (anti-Ku)

Anti-Ku were first reported in patients with PM/SSc overlap syndrome in 1994.81 Anti-Ku were originally thought to be relatively specific to SSc, although they have since been reported in sera from patients with other connective tissue diseases, such as SLE and overlap syndrome.82,83 Franceschini et al. reported that in 14 anti-Ku-positive patients a half had an overlap syndrome (five SSc/PM, one SLE/SSc/PM and one SLE/PM). Of these patients with overlap syndrome, 85% had clinical features of SSc.83 Furthermore, a large cohort study by Rozman et al. confirmed that anti-Ku were associated with myositis.84

Autoantibodies other than antinuclear antibodies in SSc

Anti-phospholipid/anti-cardiolipin antibodies (aPL, aCL)

Antiphospholipid antibodies including lupus anti-coagulant (LA) and antibodies against cardiolipin β2-glycoprotein I complex (anti-CL/β2GPI) are thought to be involved in thrombosis in patients with antiphospholipid syndrome (APS).85 SSc can be associated with vascular occlusion, thromboembolism and peripheral ischemia. Although secondary APS is often accompanied by autoimmune connective tissue diseases, particularly SLE, it is thought that secondary APS is relatively rare in SSc.86,87 On the other hand, the prevalence of aPL in SSc is approximately 20–25%.86,88–90 It was reported that the prevalence of anti-CL/β2GPI in SSc patients is approximately 10% and is significantly associated with isolated pulmonary hypertension.91 Antibodies against phosphatidylserine–prothrombin complex (anti-PS/PT) in SSc were detected in 16% (18 of 112) of patients.92 They are associated with peripheral ischemia and lung disease (pulmonary fibrosis and pulmonary hypertension) but do not appear to correlate with the severity of skin sclerosis. Sato et al.93 reported that aCL were found in 70% of the patients with generalized morphea. The presence of aPL is associated with increased spontaneous abortions in SSc patients, and higher incidences of thrombosis and pulmonary hypertension.94,95 However, there is no evidence for a pathogenic role for aPL in SSc patients to date.

Anti-platelet-derived growth factor receptor antibodies (anti-PDGFR)

Recently, Baroni et al.96 reported autoantibodies against the platelet-derived growth factor receptor (PDGFR) in patients with SSc, but not in healthy controls or patients with SLE, rheumatoid arthritis, idiopathic pulmonary fibrosis or primary Raynaud’s phenomenon. Furthermore, these autoantibodies may have a pathogenic role, because PDGFR expression is increased by pathological transforming growth factor-β signaling, and binding of PDGFR to anti-PDGFR results in amplification of the Ras-extracellular signal-regulated kinase (ERK)1/2-reactive oxygen species (ROS) cascade, leading to enhanced collagen production.96–98 However, neither an agonistic role for anti-PDGFR nor specificity of this autoantibody for SSc were found in two subsequent reports.97,99 Therefore, the role of anti-PDGFR in SSc requires further investigation.

Anti-endothelial cell antibodies (AECA)

Autoantibodies against endothelial cell antigens were originally reported in sera from patients with primary Raynaud’s phenomenon and SSc.100 They were found in 25–85% of patients with SSc, but are also seen in other connective tissue diseases.100–102 The presence of AECA was associated with digital scars or ulcers, severe Raynaud’s phenomenon, pulmonary hypertension and pulmonary fibrosis. Recently, it has been shown that higher serum AECA levels were associated with the degree of peripheral vascular injury that was assessed by nail fold capillaroscopy.103 Moreover, AECA-induced apoptosis of endothelial cells, through activation of the caspase 3 pathway and expression of fibrillin-1, was linked to subsequent autoantibody production to fibrillin-1.104 Therefore, AECA appear to play an important role in the pathogenic process of SSc-associated vascular damage.

Conclusion

Clinical features and prognoses in SSc are extremely heterogeneous and grouping patients based on autoantibody profiles can be a useful tool for clinicians. ACA are most often found in whites and are associated with limited cutaneous involvement and isolated pulmonary hypertension. Patients with ACA infrequently have pulmonary fibrosis and ACA can be a predictor of a favorable prognosis. In contrast, anti-topo I, found in patients with dSSc and pulmonary fibrosis, are associated with a poor prognosis and SSc-related mortality. Anti-RNAP are associated with diffuse cutaneous and renal involvement, but patients with anti-RNAP have a better prognosis, as renal involvement is currently curable with ACE inhibitors. Of the ANoA, anti-Th/To and anti-PM-Scl are associated with lSSc, whereas anti-U3RNP are associated with dSSc. Anti-Th/To and anti-U3RNP are predictors for a less favorable prognosis with a higher frequency of organ involvement that contains pulmonary fibrosis, pulmonary hypertension and renal crisis. Anti-Ku and anti-PM-Scl are frequently seen in SSc/PM overlap syndrome and are not SSc-specific. Anti-U1RNP are usually found in mixed connective tissue disease and are associated with Raynaud’s phenomenon, limited cutaneous involvement and myositis. Patients with anti-U1RNP generally have a favorable prognosis but fatal pulmonary hypertension can occur. To determine the clinical utility of other non-antinuclear autoantibodies, such as aPL, anti-PDGFR and AECA, more studies are needed. Importantly, both the prevalence and clinical presentation of patients with SSc are influenced by ethnicity. In summary, although it remains unclear whether autoantibodies found in patients with SSc have a direct role in the pathogenesis of disease, the identification of autoantibody profiles in SSc is helpful in assessing the clinical presentation and prognosis of disease, and for monitoring patients with SSc.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Acknowledgments
  5. References

We thank Masako Matsubara, Yuko Yamada and Tomoko Hayashi for technical assistance.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Acknowledgments
  5. References