1. Introduction
Systemic sclerosis (SSc) is a systemic autoimmune rheumatic disease (SARD) characterized by endothelial dysfunction, leading to small vessel vasculopathy, immune dysregulation, fibroblast dysfunction, and subsequent fibrosis of the skin and viscera [ 1 , 2 , 3 , 4 , 5 ]. It is a rare disease with an estimated global prevalence of 17.6 per 100,000 and an incidence rate of 1.4 per 100,000 persons per year [ 6 ]. SSc presents and evolves differently across patients, leading to progressive disability, diminished quality of life, and mortality [ 7 ].
SSc is distinguished by the presence of serum autoantibodies that target various intracellular antigens. These autoantibodies, which are present in more than 95% of patients, can be useful diagnostic indicators for SSc [ 8 ]. SSc-specific antibodies target structures in the nucleoli, nucleoplasm, or chromatin of cells that are important for cell transcription and division. The autoantibody profile of a patient with SSc does not change over time and is not affected by immunosuppressive therapy [ 8 , 9 , 10 ].
Historically, clinicians have been limited to antinuclear antibody (ANA) measured either by immunofluorescence or enzyme-linked immunosorbent assay, anti-topoisomerase (ATA, also known as anti-Scl-70) antibody, and anticentromere antibody (CENP). These autoantibodies are associated with specific clinical features and organ involvement and can inform prognosis [ 11 ]. Anti-topoisomerase I, anticentromere, and anti-RNA polymerase III antibodies were deemed vitally important in the concept of SSc [ 12 ] due to their ability to distinguish SSc from other SARD, such that they were included in the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for SSc [ 13 ].
Clinicians now have access to a larger selection of SSc-specific autoantibodies. An understanding of the epidemiology of SSc-specific antibodies, clinical associations, and prognostic value will assist clinicians in their interpretation and inform the care of SSc patients.
2. Antinuclear Antibodies (ANA)
ANA are common in the general population, occurring in up to 20% of women. The presence of an ANA is not necessarily suggestive of a pathologic process, particularly at low titers [ 14 ]. Rather, low-titer ANA are thought to reflect a state of benign autoimmunity. However, a subset (5–8%) of these individuals will progress to develop a SARD, such as SSc, Sjogren’s syndrome, or systemic lupus erythematosus [ 14 ]. ANA-positive individuals that subsequently develop a SARD have significantly increased T and B cell activation and increased LAG3 + T regulatory cells and TGF-ß1 [ 15 , 16 , 17 , 18 ]. Immunoregulation usually prevents development of rheumatic disease in ANA-positive individuals. In contrast, immunoregulation becomes impaired in individuals who progress to develop a SARD, resulting in an imbalance favoring inflammation and fibrosis.
Since the 1960s, it has been recognized that ANA are common in individuals with SSc [ 19 , 20 ]. ANA have been reported to occur in 75–95% of patients with SSc, with a sensitivity of 85% and specificity of 54% on immunofluorescence [ 21 ]. The antigen substrate that is utilized for the assay affects the specificity and sensitivity of ANA differently. An indirect immunofluorescence assay using HEp-2 cells (HEp-2 IFA) is the gold standard technique. The presence of ANA as a result of HEp-2 IFA is reported as a titer and a pattern. A clinically relevant ANA titer is 1:80 or more [ 22 ].
The staining pattern reported with ANA testing by HEp-2 IFA can also be informative. The presence of anti-Scl-70 and anti-U1-RNP antibodies in the sera creates a speckled pattern, while anti-Th/To, anti-fibrillarin (anti-U3RNP) and anti-PM/Scl antibodies create a nucleolar staining pattern. Anti-RNAP I antibodies result in nucleolar staining, while antibodies against RNAP II and III give a speckled appearance or no fluorescence [ 21 ]. With the identification of over 30 staining patterns that span many diseases, an international consensus on antinuclear antibody patterns (ICAP) has proposed a classification system to standardize the interpretation and reporting of staining patterns [ 23 ] ( Table 1 ). While the presence of ANA and staining patterns is helpful, their absence should be interpreted with caution. For example, the anti-RNAP antibodies demonstrate nucleolar staining only 30–44% of the time [ 24 , 25 ]. Thus, ANA staining patterns should not be used as the sole screening test for SSc-specific antibodies. ANA-negative SSc patients exist and may reflect a subset of SSc who have delayed progression of nailfold microangiopathy, defined by an early nailfold capillary NVC pattern [ 10 ].
In the following section, we describe individual autoantibodies observed in SSc, their clinical associations, and their predictive value. In Table 2 , we provide an overview of the sensitivity and specificity of these antibodies in people with SSc. In Table 3 , we provide an overview of their clinical associations, prognostic value, and prevalence.
2.1. Anti-Topoisomerase I Antibodies
Since anti-topoisomerase I antibodies (ATA) respond to immunoblots with a 70 kDa protein, they were originally known as anti-Scl-70 antibodies. Further research revealed that Scl-70 was a breakdown product of the full-length 100 kDa protein; thus, it was found that the name Scl-70 was misleading. ATA was detected in 15–42% of SSc patients, with 90–100% specificity [ 8 , 44 ]. ATA has sensitivity of 34% [ 21 ]. Table 2 . ATA has a poor prognosis and is highly associated with diffuse cutaneous SSc (dcSSc). Patients with limited cutaneous SSc (lcSSc) and other SARD have also been noted to have ATA. The risk of severe pulmonary fibrosis and cardiac involvement is increased in SSc patients with ATA. Additionally, tendon friction rubs, the development of digital ulcers, and joint involvement have all been associated with ATA [ 8 , 29 , 44 ] ( Table 3 ). An association with scleroderma renal crisis was reported but was not found consistently across all SSc cohorts. Furthermore, the presence of ATA in patients with Raynaud’s phenomenon is associated with a higher risk of developing SSc [ 29 ].
2.2. Anticentromere Antibodies
Anti-CENP antibodies, also known as anticentromere antibodies, were first reported in 1980. Several CENP proteins have been identified (CENP-A, CENP-B, CENP-C, and others), but CENP-B is thought to be the primary target of the anti-CENP B cell response in SSc [ 5 ]. Anti-CENP is the most commonly detected autoantibody in SSc cohorts, with a detection frequency of 20 to 38% [ 8 , 44 , 45 ]. Anti-CENP antibodies are specific to SSc and are reported to have specificity of 99.9% and sensitivity of 33% [ 26 , 27 ]. They occur less frequently in individuals of Afro-Caribbean descent compared to Caucasians [ 46 ]. Additionally, primary biliary cirrhosis, Sjogren’s syndrome, Raynaud’s phenomenon, and systemic lupus erythematosus have all been linked to anticentromere antibodies [ 47 ]. Patients with Raynaud’s phenomenon are at high risk of developing SSc if they have anti-CENP antibodies. [ 5 , 22 ]. When compared to other SSc-related antibodies, anti-CENP antibodies are typically associated with limited cutaneous SSc and have a better prognosis [ 48 , 49 ]. In this clinical subgroup of individuals, anti-CENP is associated with a higher risk of pulmonary arterial hypertension, peripheral neuropathy, and mortality [ 29 , 50 ]
2.3. Anti-Ribonucleic Acid Polymerase I, and III Antibodies
Anti-ribonucleic acid polymerase (anti-RNAP) antibodies were first described in the 1990s. Anti-RNAP I and III antibodies almost always coexist and are considered to be highly specific to SSc [ 8 ]. Anti-RNAP II antibodies are not only seen in SSc but also in systemic lupus erythematosus and overlap syndromes. Since ELISA and LIA are now more frequently used for their detection, the nucleolar speckled immunofluorescence pattern normally associated with anti-RNAP is not a sensitive tool for detecting these autoantibodies. [ 8 , 51 ]. The frequency of anti-RNAP I and III varies between 5% and 31% of SSc patients. In a recent meta-analysis, the pooled overall prevalence of anti-RNAP III was 11% [ 51 ]. RNAP antibodies consist of two subunits: the largest RP-155 and RP-11 [ 45 ]. RP-155 is associated with dcSSc and a higher risk of renal crisis. These patients may also be at higher risk of tendon friction rubs, synovitis, myositis, joint contractures, and the risk of developing malignancies. Despite the prevalence of renal involvement, survival is better in patients with anti-RNAP than in those with ATA or anti-U3RNP [ 29 ]. Although they have 100% specificity, autoantibodies against the RP-11 subunit of RNAP III are less sensitive than anti-RP-155 antibodies and do not seem to improve the diagnostic utility of anti-RP-155.
2.4. Anti-Fibrillarin (Anti-U3RNP) Antibodies
Bernstein et al. published the first report on anti-fibrillarin (anti-U3RNP) antibodies in 1982. Anti-U3-RNP antibodies specifically target a 34 kDa component of the small nucleolar ribonucleoprotein, which is located in the fibrillar area of the nucleolus and is implicated in pre-RNA processing [ 52 ]. Anti-U3RNP antibodies are detected in 41% of SSc patients. It is considered relatively specific to SSc and is mutually exclusive from CENP, ATA, and anti-RNAP [ 8 , 53 ]. They are found more frequently in African American than in Caucasian patients [ 54 ]. Anti-U3 RNP is associated with male sex, Afro-Caribbean descent, younger age at diagnosis, and higher risk of developing PAH and gastrointestinal involvement [ 55 ]. Regardless of demographics or disease type, anti-fibrillarin antibody positivity is associated with poorer survival. [ 31 ].
2.5. Anti-Th/To Ribonucleoprotein (Anti-Th/To) Antibodies
Anti-Th/To ribonucleoprotein antibodies (anti-Th/To) mainly bind to two mitochondrial RNA processing (MRP) proteins and the ribonuclease P complexes. They are present in 1–13% of SSc patients [ 12 ]. Anti-Th/To antibodies have high specificity (99%) for SSc. However, anti-Th/To antibodies have been observed in patients with rheumatoid arthritis, systemic lupus erythematosus, polymyositis, and Sjogren’s syndrome. Despite reports of up to 21% of anti-Th/To positive patients having dcSSc, the majority of these patients have lcSSc [ 56 ]. Anti-Th/To-positive SSc patients often develop pulmonary hypertension and interstitial lung disease but experience less involvement of joints and muscles [ 57 ]. Anti-Th/To antibody is a predictor for a worse prognosis [ 53 ].
2.6. Anti-U11/U12 RNP Antibodies
Low concentrations of macromolecular U11/U12 RNP complexes are present in eukaryotic cells, where they function as spliceosome components and catalyze the splicing of pre-messenger RNA into pre-mRNA introns [ 58 ]. The prevalence of anti-U11/U12 -RNP antibodies is 3.2% [ 59 ]. Anti-U11/U12 RNP antibodies have been associated with gastrointestinal manifestations, Raynaud’s phenomenon, pulmonary fibrosis, and an increased risk of mortality [ 41 , 60 ]. The presence of anti-U11/U12 RNP autoantibodies may indicate a subset of patients who are more likely to develop cancer when SSc first appears [ 61 ].
2.7. Anti-Ro/SSA Antibodies
Anti-SSA/Ro52 antibodies occur with a prevalence of 20% in SSc patients [ 62 ]. Anti-Ro52 antibody is a risk factor for a serious pulmonary outcome [ 63 ]. While one study found no correlation between the presence of anti-Ro52 antibodies and Raynaud’s phenomenon, sclerodactyly, digital ulcers, gangrene, calcinosis cutis, telangiectasia, or esophageal dysmotility [ 63 ], anti-Ro52 antibody is predictor of poor survival in SSc [ 64 ].
2.8. Anti-Ku Antibodies
Initially discovered in individuals with scleroderma–polymyositis overlap syndrome, anti-Ku antibodies were first reported in 1981 by Mimori et al. Ku is a DNA-binding protein involved in DNA repair, which is important for the non-homologous end-joining pathway’s ability to repair double-stranded DNA breaks [ 36 ]. In a recent international cohort, anti-Ku antibodies were rarely found in only 1.1% of SSc patients. Anti-Ku is more commonly detected in limited SSc patients with overlap disorders (myositis or lupus) [ 43 , 65 , 66 ]. Anti-Ku positivity is associated with myositis and interstitial lung disease (ILD), while vascular involvement is less prevalent [ 67 ]. With regard to prognosis, no survival difference has been associated with this autoantibody [ 67 ].
2.9. Anti-PM/Scl Antibodies
Anti-PM/Scl antibodies are a heterogeneous group of autoantibodies directed to several proteins of the nucleolar PM/Scl macromolecular complex. The two main autoantigenic protein components were identified and named PM/Scl-75 and PM/Scl-100, based on their molecular weights [ 68 ]. Anti-PM/Scl have sensitivity of 12.5% and specificity of 96.9% for SSc [ 69 ].
2.10. Anti-PM75 Antibodies
Anti-PM/Scl 75 antibodies occur with a prevalence of 10.4% [ 69 ]. Anti-PM75 antibodies are associated with high rates of calcinosis cutis and gastrointestinal manifestations, including gastroesophageal reflux disease, dysphagia, small intestinal bacterial overgrowth, and fecal incontinence. ILD was also prevalent in SSc patients with anti-PM75, second only to ATA-positive patients. Pulmonary hypertension is reported to be the clinical feature most commonly associated with the anti-PM75 antibody [ 70 ].
2.11. Anti-PM100 Antibodies
Anti-PM/Scl 100 antibodies have a prevalence of 7.1% [ 69 ]. Anti-PM100 is more associated with calcinosis rather than gastrointestinal manifestation. ILD was also less frequent compared to the anti-PM75 [ 70 ]. Patients with anti-PM100 antibodies had higher survival rates [ 70 ].
2.12. Anti-hUBF/NOR-90 Antibodies
The anti-NOR90 antibody, a nucleolar type of ANA, is found in 6.1% of SSc patients [ 71 ]. However, this antibody tends to be less specific for SSc and is reported in other SARD, such as systemic lupus erythematosus, Sjogren’s syndrome, and rheumatoid arthritis [ 39 ]. Anti-NOR90 antibodies may be a biomarker for idiopathic interstitial pneumonia with features of systemic sclerosis. Anti-NOR90 antibodies are associated with the occurrence of arthritis/arthralgia, sicca symptoms, and Raynaud’s phenomenon [ 72 , 73 ]. Systemic sclerosis with anti-NOR90 antibodies can be complicated by interstitial lung disease and cancer [ 40 ]. Anti-NOR-90 antibodies may be associated with a favorable prognosis [ 71 ].
2.13. Anti-RuvBL1 and RuvBL2 Antibodies
RuvBL1/2 is an important modulator of transcriptional activation and protein assembly and is essential for cell proliferation. It is located in the nucleus but can also be present in the cytoplasm [ 74 ]. Although only 1–2% of patients have anti-RuvBL1/2, it is highly specific to SSc. The relationship of anti-RuvBL1 and RuvBL2 with older onset age, more frequent diffuse skin and skeletal muscle involvement, male sex, and overlap myositis are its distinguishing features [ 75 ].
2.14. Platelet-Derived Growth Factor Stimulatory Antibodies (PDGFs)
Platelet-derived growth factor stimulatory (PDGF) antibodies are the primary mitogens for cells of mesenchymal and neuroectodermal origin. PDGF, first described in the 1970s as a serum factor that stimulates smooth muscle cell proliferation, is now one of the best-characterized growth factor receptor systems [ 76 ]. SSc appears to have a distinctive signature that stimulates autoantibodies against PDGFR. Their biological effect on fibroblasts may contribute to the pathogenesis of the disease. [ 77 ].
3. Myositis Autoantibodies
Myositis autoantibodies have traditionally been divided into subgroups of myositis-specific and myositis-associated antibodies. Myositis-specific antibodies are predominantly found in patients with polymyositis or dermatomyositis, while myositis-associated antibodies are usually found in patients with overlapping features of myositis and other SARDs [ 78 ].
3.1. Myositis-Specific Antibodies
Anti-synthetase antibodies target aminoacyl tRNA synthetases. The tRNA synthetases are a family of cytoplasmic enzymes that load specific amino acids onto their cognate tRNA to form an aminoacyl tRNA. There are eight anti-tRNA synthetase autoantibodies. Anti-Jo-1 antibody (directed against histidyl-tRNA synthetase) is the most common myositis-specific antibody in adults with idiopathic inflammatory myopathy, with a frequency of 9–24%. Anti-PL-12 and antibodies to the OJ, EJ, PL-7, PL-12, KS, Zo, and Ha antigens are less common [ 79 ]. The anti-SRP antibody is directed at the signal recognition particle (SRP), which participates in the translocation of newly synthesized proteins into the endoplasmic reticulum [ 80 ] The anti-MDA5 antibody is directed against RNA helicase encoded by the melanoma differentiation-associated gene 5 (MDA5). The anti-NXP-2 antibody is directed against nuclear matrix protein 2 (NXP-2) involved in transcriptional regulation. The anti-Mi-2 antibody is directed against a helicase involved in transcriptional activation. The anti-SAE antibody is directed against the small ubiquitin-like modifier activating enzyme (SAE) that regulates gene transcription.
Myositis-specific autoantibodies are only positive in 20 to 40 percent of myositis patients; therefore, a negative test does not rule out a diagnosis. Rather, a positive antibody informs the type of myositis and disease trajectory. While these antibodies have been associated with polymyositis and antisynthetase syndrome, their prevalence, clinical associations, and prognostic value in SSc is uncertain. Similarly, many antibodies have been associated with malignancy.
3.2. Myositis-Associated Antibodies
In contrast, myositis-associated autoantibodies are present in patients with SARD that can be associated with myositis. The presence of anti-Ro/SSA, anti-La/SSB, anti-Sm, or anti-ribonucleoprotein (RNP) antibodies in a patient with myositis suggests an association or overlap with another SARD. Anti-Ro52 antibodies are common in patients with antisynthetase antibodies, and anti-Ro60 and anti-La/SSB may be seen with other myositis-specific antibodies.
Myositis autoantibodies have rarely been described in SSc [ 81 , 82 ]. A recent study conducted in France showed that the prevalence of myositis-specific antibodies was 8.0% and that of myositis-associated autoantibodies was 9.7%. However, the prevalence of each antibody was low, at less than 5%. Myositis-associated autoantibodies positivity was associated with ILD and myositis, but this study showed no clinical associations with myositis-specific antibodies positivity [ 38 , 83 ].
4. Interpreting Their Operating Characteristics
It is important to remember that the sensitivity and specificity of these antibodies are affected by their prevalence and the choice of the comparator group. For example, anti-U3 RNP/fibrillarin, anti-Th/To, anti-PM/Scl, and anti-U11/U12 RNP are infrequent in the general population and other SARDs [ 8 ]. In SSc cohorts, the sensitivity and specificity of these antibodies may differ depending on several factors, such as race, area of origin, immunogenic markers, and the autoantigen immunoassay they were detected with [ 8 , 45 ] ( Table 2 ). A recent study from the Netherlands compared the detection of SSc-specific autoantibodies through various diagnostic tests. Seventy-nine percent of patients tested positive for SSc autoantibodies in at least one diagnostic test. SSc-specific autoantibodies included in the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria showed a high degree of concordance (antitopoisomerase, anticentromere antibody, and anti-RNA polymerase III). PM/Scl, Ku, fibrillarin, and Th-To antibodies demonstrated less concordance. A minority of patients were ATA and ARA positive [ 2 ].
5. Are systemic Sclerosis-Associated Antibodies Mutually Exclusive?
The SSc-specific autoantibodies are thought to be mutually exclusive [ 26 ], but there is a small body of literature on their coexistence. In a recent study of 2799 SSc patients conducted in England, 5% had more than one SSc-specific autoantibody [ 84 ]. ATA and ACA expression are not completely mutually exclusive, but their coexistence is rare (<1% of patients with SSc). Patients with both autoantibodies often have diffuse cutaneous disease and display immunogenetic features of both antibody-defined subsets of SSc [ 85 ]. In another study of 4687 patients from the EUSTAR database, 29 patients (0.6%) were documented as double positive for both ATA and CENP antibodies. Sera from 14 patients were available for central reanalysis by immunofluorescence, enzyme immunoassay, and immunoblot to confirm antibody status. Eight patients were confirmed to contain both autoantibodies. The prevalence of cutaneous and visceral manifestations in double-positive antibody patients was similar to single-positive antibody patients [ 86 ]. In an Italian cohort of 210 SSc patients, in which a commercially available LIA was used for the simultaneous detection of 13 SSc-associated autoantibodies, except for anti-Ro52/TRIM21 (specificity of 50%), all autoantibodies were very specific (from 93.3% anti-PM/Scl-75 to 100% anti-PDGFR, AFA, and anti-RP-11) for SSc. Anti-Ku was associated with another autoantibody in 0.4% of positive patients, and anti-PM/Scl-110 was associated with another autoantibody in 0.42% of patients [ 45 ].
6. Using Antibodies to Identify Subsets of SSc Patients
Given the association of specific organ involvement, outcomes, and antibodies, there are international initiatives to develop classification criteria to identify subsets of SSc patients [ 86 , 87 , 88 ]. The Very Early Diagnosis of Systemic Sclerosis (VEDOSS) criteria identify a subset of patients based on the presence of RP, puffy fingers, antinuclear antibodies, and capillaroscopy or SSc-specific antibodies [ 89 ]. Using the Australian Scleroderma Interest Group and the Canadian Scleroderma Research Group cohort data, three subsets of SSc were proposed [ 90 ]. Subset 1 is characterized by digital ulcers, pitting scars, and anti-topoisomerase I antibodies. Subset 2 is characterized by diffuse skin involvement, tendon friction rubs, and anti-RNA polymerase III antibodies. Subset 3 is characterized by limited or no skin involvement and anticentromere antibodies [ 91 ]. Other researchers have proposed a simplified system combining the extent of skin involvement and SSc-specific antibodies [ 87 ]. A reliable, responsive, and valid SSc subset system using an antibody profile could be used to identify patients most likely to derive a therapeutic benefit, and as a cohort enrichment strategy for trials of therapeutic agents [ 90 , 91 ].
7. Summary
Clinicians have increasing access to advanced autoantibody profiling in the assessment of patients with SSc. The staining pattern on ANA testing by indirect immunofluorescence assay on Hep-2 cells can provide a clue to the SSc-specific antibodies that may be present and that warrant further investigation. This narrative review provides up-to-date, practical information for the practicing clinician who cares for people with SSc. The presence of SSc-specific antibodies can inform the prediction of patients with Raynaud’s phenomenon who have an increased probability of developing SSc and warrant close follow-up. The presence of SSc-specific antibodies can assist with making a clinical diagnosis, can contribute to classification of SSc for research purposes, can guide monitoring for specific internal organ manifestations, and can inform prognosis.
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Author Contributions
Conceptualization, K.A. and Z.A.; methodology, Z.A.; software, K.A.; validation, K.A., Z.A. and S.R.J.; formal analysis, K.A.; investigation, K.A.; resources, S.R.J.; data curation, Z.A.; writing—original draft preparation, K.A.; writing—review and editing, Z.A.; visualization, S.R.J.; supervision, S.R.J.; project administration, S.R.J.; funding acquisition, S.R.J. All authors have read and agreed to the published version of the manuscript.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Not applicable.
Conflicts of Interest
The authors declare no conflict of interest.
References
1. Distler O. Assassi S. Cottin V. Cutolo M. Danoff S.K. Denton C.P. Distler J.H. Hoffmann-Vold A.-M. Johnson S.R. Ladner U.M. Predictors of progression in systemic sclerosis patients with interstitial lung disease Eur. Respir. J. 2020 55 1902026 10.1183/13993003.02026-2019 32079645 PMC7236865
2. Ruaro B. Soldano S. Smith V. Paolino S. Contini P. Montagna P. Pizzorni C. Casabella A. Tardito S. Sulli A. Correlation between circulating fibrocytes and dermal thickness in limited cutaneous systemic sclerosis patients: A pilot study Rheumatol. Int. 2019 39 1369 1376 10.1007/s00296-019-04315-7 31056725
3. Caforio A.L.P. De Luca G. Baritussio A. Seguso M. Gallo N. Bison E. Cattini M.G. Pontara E. Gargani L. Pepe A. Serum Organ-Specific Anti-Heart and Anti-Intercalated Disk Autoantibodies as New Autoimmune Markers of Cardiac Involvement in Systemic Sclerosis: Frequency, Clinical and Prognostic Correlates Diagnostics 2021 11 2165 10.3390/diagnostics11112165 34829512 PMC8625508
4. Ruaro B. Baratella E. Confalonieri P. Wade B. Marrocchio C. Geri P. Busca A. Pozzan R. Andrisano A.G. Cova M.A. High-Resolution Computed Tomography: Lights and Shadows in Improving Care for SSc-ILD Patients Diagnostics 2021 11 1960 10.3390/diagnostics11111960 34829307 PMC8617987
5. Bairkdar M. Rossides M. Westerlind H. Hesselstrand R. Arkema E.V. Holmqvist M. Incidence and prevalence of systemic sclerosis globally: A comprehensive systematic review and meta-analysis Rheumatology 2021 60 3121 3133 10.1093/rheumatology/keab190 33630060 PMC8516513
6. Johnson S.R. Glaman D.D. Schentag C.T. Lee P. Quality of life and functional status in systemic sclerosis compared to other rheumatic diseases J. Rheumatol. 2006 33 1117 1122 16622903
7. Mehra S. Walker J. Patterson K. Fritzler M.J. Autoantibodies in systemic sclerosis Autoimmun. Rev. 2013 12 340 354 10.1016/j.autrev.2012.05.011 22743034
8. Benyamine A. Bertin D. Resseguier N. Heim X. Bermudez J. Launay D. Dubucquoi S. Hij A. Farge D. Lescoat A. Quantification of Antifibrillarin (anti-U3 RNP) Antibodies: A New Insight for Patients with Systemic Sclerosis Diagnostics 2021 11 1064 10.3390/diagnostics11061064 34207757 PMC8226926
9. Sulli A. Ruaro B. Smith V. Pizzorni C. Zampogna G. Gallo M. Cutolo M. Progression of nailfold microvascular damage and antinuclear antibody pattern in systemic sclerosis J. Rheumatol. 2013 40 634 639 10.3899/jrheum.121089 23457379
10. Arnett F.C. Is scleroderma an autoantibody mediated disease? Curr. Opin. Rheumatol. 2006 18 579 581 10.1097/01.bor.0000245726.33006.c3 17053501
11. Johnson S.R. Naden R.P. Fransen J. Hoogen F.V.D. Pope J.E. Baron M. Tyndall A. Matucci-Cerinic M. Denton C.P. Distler O. Multicriteria decision analysis methods with 1000Minds for developing systemic sclerosis classification criteria J. Clin. Epidemiol 2014 67 706 714 10.1016/j.jclinepi.2013.12.009 24721558 PMC4134523
12. Van den Hoogen F. Khanna D. Fransen J. Johnson S.R. Baron M. Tyndall A. Matucci-Cerinic M. Naden R.P. Medsger T.A. Jr. Carreira P.E. 2013 classification criteria for systemic sclerosis: An American college of rheumatology/European league against rheumatism collaborative initiative Ann. Rheum. Dis. 2013 72 1747 1755 10.1136/annrheumdis-2013-204424 24092682
13. Wither J. Johnson S.R. Liu T. Noamani B. Bonilla D. Lisnevskaia L. Silverman E. Bookman A. Landolt-Marticorena C. Presence of an interferon signature in individuals who are anti-nuclear antibody positive lacking a systemic autoimmune rheumatic disease diagnosis Arthritis Res. Ther. 2017 19 41 10.1186/s13075-017-1243-y 28245862 PMC5331647
14. Baglaenko Y. Chang N.-H. Johnson S.R. Hafiz W. Manion K. Ferri D. Noamani B. Bonilla D. Rusta-Sellehy S. Lisnevskaia L. The presence of anti-nuclear antibodies alone is associated with changes in B cell activation and T follicular helper cells similar to those in systemic autoimmune rheumatic disease Arthritis Res. Ther. 2018 20 264 10.1186/s13075-018-1752-3 30486869 PMC6263058
15. Muñoz-Grajales C. Prokopec S.D. Johnson S.R. Touma Z. Ahmad Z. Bonilla D. Hiraki L. Bookman A. Boutros P.C. Chruscinski A. Serological abnormalities that predict progression to systemic autoimmune rheumatic diseases in antinuclear antibody-positive individuals Rheumatology 2022 61 1092 1105 10.1093/rheumatology/keab501 34175923 PMC8889298
16. Gupta R. Vanlieshout E. Manion K. Bonilla D. Kim M. Muñoz-Grajales C. Nassar C. Johnson S.R. Hiraki L.T. Ahmad Z. Altered Balance of Pro-Inflammatory Immune Cells to T Regulatory Cells Differentiates Symptomatic From Asymptomatic Individuals With Anti-Nuclear Antibodies Front. Immunol. 2022 13 886442 10.3389/fimmu.2022.886442 35844549 PMC9279569
17. Hafiz W. Nori R. Bregasi A. Noamani B. Bonilla D. Lisnevskaia L. Silverman E. Bookman A.A.M. Johnson S.R. Landolt-Marticorena C. Fatigue severity in anti-nuclear antibody-positive individuals does not correlate with pro-inflammatory cytokine levels or predict imminent progression to symptomatic disease Arthritis Res. Ther. 2019 21 223 10.1186/s13075-019-2013-9 31685018 PMC6827224
18. Fennell R.H. Jr. Rodnan G.P. Vazquez J.J. Variability of tissue-localizing properties of serum from patients with different disease states Lab. Investig. 1962 2 24 31 13892284
19. Beck J.S. Anderson J.R. Gray K.G. Rowell N.R. Antinuclear and precipitating autoantibodies in progressive systemic sclerosis Lancet 1963 2 1188 1190 10.1016/S0140-6736(63)92920-9 14072937
20. Solomon D.H. Kavanaugh A.J. Schur P.H. Evidence-based guidelines for the use of immunologic tests: Antinuclear antibody testing Arthritis Rheum. 2002 47 434 444 10.1002/art.10561 12209492
21. Leuchten N. Hoyer A. Brinks R. Schoels M. Schneider M. Smolen J. Johnson S.R. Daikh D. Dörner T. Aringer M. Performance of Antinuclear Antibodies for Classifying Systemic Lupus Erythematosus: A Systematic Literature Review and Meta-Regression of Diagnostic Data Arthritis Care. Res. 2018 70 428 438 10.1002/acr.23292 28544593
22. Chan E.K.L. von Mühlen C.A. Fritzler M.J. Damoiseaux J. Infantino M. Klotz W. Satoh M. Musset L. La Torre I.G.-D. Carballo O.G. The International Consensus on ANA Patterns (ICAP) in 2021-The 6th Workshop and Current Perspectives J. Appl. Lab. Med. 2022 7 322 330 10.1093/jalm/jfab140 34996073
23. Yamasaki Y. Honkanen-Scott M. Hernandez L. Ikeda K. Barker T. Bubb M.R. Narain S. Richards H.B. Chan E. Reeves W.H. Nucleolar staining cannot be used as a screening test for the scleroderma marker anti-RNA polymerase I/III antibodies Arthritis Rheum. 2006 54 3051 3056 10.1002/art.22043 16948135
24. Parker J.C. Burlingame R.W. Webb T.T. Bunn C.C. Anti-RNA polymerase III antibodies in patients with systemic sclerosis detected by indirect immunofluorescence and ELISA Rheumatology 2008 47 976 979 10.1093/rheumatology/ken201 18499715 PMC2430219
25. Reveille J.D. Solomon D.H. Evidence-based guidelines for the use of immunologic tests: Anticentromere, Scl-70, and nucleolar antibodies Arthritis Rheum. 2003 49 399 412 10.1002/art.11113 12794797
26. Spencer-Green G. Alter D. Welch H.G. Test performance in systemic sclerosis: Anti-centromere and anti-Scl-70 antibodies Am. J. Med. 1997 103 242 248 10.1016/S0002-9343(97)00023-5 9316557
27. Satoh T. Ishikawa O. Ihn H. Endo H. Kawaguchi Y. Sasaki T. Goto D. Takahashi K. Takahashi H. Misaki Y. Clinical usefulness of anti-RNA polymerase III antibody measurement by enzyme-linked immunosorbent assay Rheumatology 2009 48 1570 1574 10.1093/rheumatology/kep290 19808694
28. Steen V.D. Autoantibodies in systemic sclerosis Semin. Arthritis Rheum. 2005 35 35 42 10.1016/j.semarthrit.2005.03.005 16084222
29. Gehring I. Sjölander S. Höpfl P. Swiniarski S. Iversen L.V. Gallo G. AB0673 Testing for antibodies specific to fibrillarin (U3 RNP) shows added value for diagnosis of systemic sclerosis Ann. Rheum. Dis. 2017 76 (Suppl. S2) 1288
30. Mejia Otero C. Assassi S. Hudson M. Mayes M.D. Estrada-Y-Martin R. Pedroza C. Mills T.W. Walker J. Baron M. Stevens W. Antifibrillarin Antibodies Are Associated with Native North American Ethnicity and Poorer Survival in Systemic Sclerosis J. Rheumatol. 2017 44 799 805 10.3899/jrheum.160574 28365584 PMC5457664
31. Choi M.Y. Fritzler M.J. Progress in understanding the diagnostic and pathogenic role of autoantibodies associated with systemic sclerosis Curr. Opin. Rheumatol. 2016 28 586 594 10.1097/BOR.0000000000000325 27387266 PMC5029444
32. Tangri V. Hewson C. Baron M. Bonner A. Fritzler M. Pope J.E. Associations with Organ Involvement and Autoantibodies in Systemic Sclerosis: Results from the Canadian Scleroderma Research Group (CSRG)* Open J. Rheumatol. Autoimmune Dis. 2013 3 113 118 10.4236/ojra.2013.32017
33. Graf S.W. Hakendorf P. Lester S. Patterson K. Walker J. Smith M.D. Ahern M.J. Roberts-Thomson P. South Australian Scleroderma Register: Autoantibodies as predictive biomarkers of phenotype and outcome Int. J. Rheum. Dis. 2012 15 102 109 10.1111/j.1756-185X.2011.01688.x 22324953
34. Lee A. Patterson K.A. Tan D.J. Wilson M.E. Proudman S.M. Stevens W. Nikpour M. Sahhar J. Ngian G.-S. Roddy J. Anti-Ro52/TRIM21 is independently associated with pulmonary arterial hypertension and mortality in a cohort of systemic sclerosis patients Scand. J. Rheumatol. 2021 50 469 474 10.1080/03009742.2021.1887927 33851896
35. Belizna C. Henrion D. Beucher A. Lavigne C. Ghaali A. Lévesque H. Anti-Ku antibodies: Clinical, genetic and diagnostic insights Autoimmun. Rev. 2010 9 691 694 10.1016/j.autrev.2010.05.020 20621654
36. Breda S. Codullo V. Fusetti C. Caporali R. Montecucco C. SAT0217 Anti- RO/SSA Antibodies in Systemic Sclerosis: Frequency and Clinical Associations in a Monocentric Referral Cohort Ann. Rheum. Dis. 2013 72 (Suppl. S3) A654 10.1136/annrheumdis-2013-eular.1943
37. Leurs A. Dubucquoi S. Machuron F. Balden M. Renaud F. Rogeau S. Lopez B. Lambert M. Morell-Dubois S. Maillard H. Extended myositis-specific and -associated antibodies profile in systemic sclerosis: A cross-sectional study Joint Bone Spine 2021 88 105048 10.1016/j.jbspin.2020.06.021 32653653
38. Dagher J.H. Scheer U. Voit R. Grummt I. Lonzetti L. Raymond Y. Senécal J.L. Autoantibodies to NOR 90/hUBF: Longterm clinical and serological followup in a patient with limited systemic sclerosis suggests an antigen driven immune response J. Rheumatol. 2002 29 1543 1547 12136917
39. Yamashita Y. Yamano Y. Muro Y. Ogawa-Momohara M. Takeichi T. Kondoh Y. Akiyama M. Clinical significance of anti-NOR90 antibodies in systemic sclerosis and idiopathic interstitial pneumonia Rheumatology 2021 61 1709 1716 10.1093/rheumatology/keab575 34282441
40. Mahler M. Satoh M. Fritzler M. Anti-Th/To Antibodies: Association With Lung Disease and Potential Protection From Systemic Sclerosis-Related Cancer? Comment on the Article by Mecoli et al Arthritis Rheumatol. 2021 73 545 546 10.1002/art.41560 33079480
41. Kayser C. Fritzler M.J. Autoantibodies in systemic sclerosis: Unanswered questions Front. Immunol. 2015 6 167 10.3389/fimmu.2015.00167 25926833 PMC4397862
42. Rozman B. Cucnik S. Sodin-Semrl S. Czirjak L. Varju C. Distler O. Huscher D. Aringer M. Steiner G. Matucci-Cerinic M. Prevalence and clinical associations of anti-Ku antibodies in patients with systemic sclerosis: A European EUSTAR-initiated multi-centre case-control study Ann. Rheum. Dis. 2008 67 1282 1286 10.1136/ard.2007.073981 18063672
43. Ho K.T. Reveille J.D. The clinical relevance of autoantibodies in scleroderma Arthritis Res. Ther. 2003 5 80 93 12718748 10.1186/ar628 PMC165038
44. Villalta D. Imbastaro T. Di Giovanni S. Lauriti C. Gabini M. Turi M.C. Bizzaro N. Diagnostic accuracy and predictive value of extended autoantibody profile in systemic sclerosis Autoimmun. Rev. 2012 12 114 120 10.1016/j.autrev.2012.07.005 22776784
45. Al-Sheikh H. Ahmad Z. Johnson S.R. Ethnic Variations in Systemic Sclerosis Disease Manifestations, Internal Organ Involvement, and Mortality J. Rheumatol. 2019 46 1103 1108 10.3899/jrheum.180042 30824634
46. Alharbi S. Ahmad Z. Bookman A.A. Touma Z. Sanchez-Guerrero J. Mitsakakis N. Johnson S.R. Epidemiology and Survival of Systemic Sclerosis-Systemic Lupus Erythematosus Overlap Syndrome J. Rheumatol. 2018 45 1406 1410 10.3899/jrheum.170953 30008448
47. Nevskaya T. Pope J.E. Turk M.A. Shu J. Marquardt A. Hoogen F.V.D. Khanna D. Fransen J. Matucci-Cerinic M. Baron M. Systematic Analysis of the Literature in Search of Defining Systemic Sclerosis Subsets J. Rheumatol. 2021 48 1698 1717 10.3899/jrheum.201594 33993109 PMC10613330
48. Johnson S.R. Feldman B.M. Hawker G.A. Classification criteria for systemic sclerosis subsets J. Rheumatol. 2007 34 1855 1863 17696271
49. AlMehmadi B.A. To F.Z. Anderson M.A. Johnson S.R. Epidemiology and Treatment of Peripheral Neuropathy in Systemic Sclerosis J. Rheumatol. 2021 48 1839 1849 10.3899/jrheum.201299 34210833
50. Sobanski V. Dauchet L. Lefèvre G. Lambert M. Morell-Dubois S. Sy T. Hachulla E. Hatron P.-Y. Launay D. Dubucquoi S. Prevalence of anti-RNA polymerase III antibodies in systemic sclerosis: New data from a French cohort and a systematic review and meta-analysis Arthritis Rheumatol. 2014 66 407 417 10.1002/art.38219 24504813
51. Tall F. Dechomet M. Riviere S. Cottin V. Ballot E. Tiev K.P. Montin R. Morin C. Chantran Y. Grange C. The Clinical Relevance of Antifibrillarin (anti-U3-RNP) Autoantibodies in Systemic Sclerosis Scand. J. Immunol. 2017 85 73 79 10.1111/sji.12510 27864990
52. Hamaguchi Y. Autoantibody profiles in systemic sclerosis: Predictive value for clinical evaluation and prognosis J. Dermatol. 2010 37 42 53 10.1111/j.1346-8138.2009.00762.x 20175839
53. Steen V. Domsic R.T. Lucas M. Fertig N. Medsger T.A. A clinical and serologic comparison of African American and Caucasian patients with systemic sclerosis Arthritis Rheum. 2012 64 2986 2994 10.1002/art.34482 22576620 PMC3557827
54. Cavazzana I. Vojinovic T. Airo’ P. Fredi M. Ceribelli A. Pedretti E. Lazzaroni M.G. Garrafa E. Franceschini F. Systemic Sclerosis-Specific Antibodies: Novel and Classical Biomarkers Clin. Rev. Allergy Immunol. 2022 1 19 10.1007/s12016-022-08946-w PMC10167150 35716254
55. Mitri G.M. Lucas M. Fertig N. Steen V.D. Medsger T.A. A comparison between anti-Th/To- and anticentromere antibody-positive systemic sclerosis patients with limited cutaneous involvement Arthritis Rheum. 2003 48 203 209 10.1002/art.10760 12528120
56. Suresh S. Charlton D. Snell E.K. Laffoon M. Medsger T.A. Jr. Zhu L. Domsic R.T. Development of Pulmonary Hypertension in Over One-Third of Patients With Th/To Antibody-Positive Scleroderma in Long-Term Follow-U Arthritis Rheumatol. 2022 74 1580 1587 10.1002/art.42152 35467794 PMC9477491
57. Wassarman K.M. Steitz J.A. The low-abundance U11 and U12 small nuclear ribonucleoproteins (snRNPs) interact to form a two-snRNP complex Mol. Cell. Biol. 1992 12 1276 1285 1372090 10.1128/mcb.12.3.1276 PMC369560
58. Fertig N. Domsic R.T. Rodriguez-Reyna T. Kuwana M. Lucas M. Medsger T.A. Jr. Feghali-Bostwick C.A. Anti-U11/U12 RNP antibodies in systemic sclerosis: A new serologic marker associated with pulmonary fibrosis Arthritis Rheum. 2009 61 958 965 10.1002/art.24586 19565553 PMC2739404
59. Callejas-Moraga E.L. Guillén-Del-Castillo A. Perurena-Prieto J. Sanz-Martínez M.T. Fonollosa-Pla V. Lorite-Gomez K. Severino A. Bellocchi C. Beretta L. Mahler M. Anti-RNPC-3 antibody predicts poor prognosis in patients with interstitial lung disease associated to systemic sclerosis Rheumatology 2021 61 154 162 10.1093/rheumatology/keab279 33742673
60. Hoogenraad C.C. Wulf P. Schiefermeier N. Stepanova T. Galjart N. Small J.V. Grosveld F. De Zeeuw C.I. Akhmanova A. Bicaudal D induces selective dynein-mediated microtubule minus end-directed transport Embo. J. 2003 22 6004 6015 10.1093/emboj/cdg592 14609947 PMC275447
61. Defendenti C. Atzeni F. Spina M.F. Grosso S. Cereda A. Guercilena G. Bollani S. Saibeni S. Puttini P.S. Clinical and laboratory aspects of Ro/SSA-52 autoantibodies Autoimmun. Rev. 2011 10 150 154 10.1016/j.autrev.2010.09.005 20854935
62. Meridor K. Sagy I. Molad Y. Anti-Ro/SS-A antibody is associated with worse pulmonary outcome and reduced overall survival in systemic sclerosis Mod. Rheumatol. 2022 32 1086 1093 10.1093/mr/roab118 34927207
63. Wodkowski M. Hudson M. Proudman S. Walker J. Stevens W. Nikpour M. Assassi S. Mayes M.D. Wang M. Baron M. Monospecific anti-Ro52/TRIM21 antibodies in a tri-nation cohort of 1574 systemic sclerosis subjects: Evidence of an association with interstitial lung disease and worse survival Clin. Exp. Rheumatol. 2015 33 (Suppl. S91) S131 S135 26315678
64. Moinzadeh P. Aberer E. Ahmadi-Simab K. Blank N. Distler J.H.W. Fierlbeck G. Genth E. Guenther C. Hein R. Henes J. Disease progression in systemic sclerosis-overlap syndrome is significantly different from limited and diffuse cutaneous systemic sclerosis Ann. Rheum. Dis. 2015 74 730 737 10.1136/annrheumdis-2013-204487 24389298 PMC4392314
65. Cavazzana I. Fredi M. Taraborelli M. Quinzanini M. Tincani A. Franceschini F. A subset of systemic sclerosis but not of systemic lupus erythematosus is defined by isolated anti-Ku autoantibodies Clin. Exp. Rheumatol. 2013 31 (Suppl. S76) 118 121 23910615
66. Hoa S. Hudson M. Troyanov Y. Proudman S. Walker J. Stevens W. Nikpour M. Assassi S. Mayes M.D. Wang M. Single-specificity anti-Ku antibodies in an international cohort of 2140 systemic sclerosis subjects: Clinical associations Medicine 2016 95 e4713 10.1097/MD.0000000000004713 PMC5008592 27583908
67. Blüthner M. Bautz F.A. Cloning and characterization of the cDNA coding for a polymyositis-scleroderma overlap syndrome-related nucleolar 100-kD protein J. Exp. Med. 1992 176 973 980 10.1084/jem.176.4.973 1383382 PMC2119404
68. Hanke K. Brückner C.S. Dähnrich C. Huscher D. Komorowski L. Meyer W. Janssen A. Backhaus M. Becker M. Kill A. Antibodies against PM/Scl-75 and PM/Scl-100 are independent markers for different subsets of systemic sclerosis patients Arthritis Res. Ther. 2009 11 R22 10.1186/ar2614 19220911 PMC2688254
69. Wodkowski M. Walker J. Stevens W. Assassi S. Mayes M.D. Baron M. Fritzler M.J. Wodkowski M. Proudman S. Nikpour M. Clinical correlates of monospecific anti-PM75 and anti-PM100 antibodies in a tri-nation cohort of 1574 systemic sclerosis subjects Autoimmunity 2015 48 542 551 10.3109/08916934.2015.1077231 26334795
70. Valero C. Baldivieso J.P. Llorente I. Vicente-Rabaneda E.F. Pinedo L.E. de Vicuna R.G. Alfranca M.A. Castañeda S. AB0427 ANTI-NOR90 autoantibodies: Favorable or unfavorable prognosis? Ann. Rheum. Dis. 2021 80 (Suppl. S1) 1241 1242 10.1136/annrheumdis-2021-eular.1477
71. Biglia A. Dourado E. Palterer B. Parronchi P. Pellico M.R. Zanframundo G. Matias P.A.R. Martins P. Miranda A. Da Fonseca J.E.C. POS0863 ANTI-NOR90 antibodies in the setting of connective tissue disease: Clinical significance and comparison with a cohort of patients with systemic sclerosis Ann. Rheum. Dis. 2022 81 (Suppl. S1) 725 726 10.1136/annrheumdis-2022-eular.1636
72. Koutsianas C. Levasseur K. Rutter M. Webber C. Bhole M.V. Bell C. Douglas K.M. 204 A lost-to-follow-up autoantibody for the diagnosis of autoimmune disease: Prevalence and clinical characteristics of anti-NOR90/hUBF positive patients Rheumatology 2018 57 (Suppl. S3) key075-428 10.1093/rheumatology/key075.428
73. Zaarur N. Xu X. Lestienne P. Meriin A.B. McComb M. E Costello C. Newnam G.P. Ganti R. Romanova N.V. Shanmugasundaram M. RuvbL1 and RuvbL2 enhance aggresome formation and disaggregate amyloid fibrils Embo. J. 2015 34 2363 2382 10.15252/embj.201591245 26303906 PMC4570522
74. Kaji K. Fertig N. Hoshino K. Lucas M. Schnure A. Ogawa F. Medsger T.A. Satoh T. Hamaguchi Y. Hasegawa M. Autoantibodies to RuvBL1 and RuvBL2: A novel systemic sclerosis-related antibody associated with diffuse cutaneous and skeletal muscle involvement Arthritis Care Res. 2014 66 575 584 10.1002/acr.22163 24023044
75. Betsholtz C. Biology of platelet-derived growth factors in development Birth Defects Res. C Embryo Today 2003 69 272 285 10.1002/bdrc.10030 14745969
76. Baroni S.S. Santillo M. Bevilacqua F. Luchetti M. Spadoni T. Mancini M. Fraticelli P. Sambo P. Funaro A. Kazlauskas A. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis N. Engl. J. Med. 2006 354 2667 2676 10.1056/NEJMoa052955 16790699
77. Betteridge Z. Tansley S. Shaddick G. Chinoy H. Cooper R. New R. Lilleker J. Vencovsky J. Chazarain L. Danko K. Frequency, mutual exclusivity and clinical associations of myositis autoantibodies in a combined European cohort of idiopathic inflammatory myopathy patients J. Autoimmun. 2019 101 48 55 10.1016/j.jaut.2019.04.001 30992170 PMC6580360
78. Betteridge Z. McHugh N. Myositis-specific autoantibodies: An important tool to support diagnosis of myositis J. Intern. Med. 2016 280 8 23 10.1111/joim.12451 26602539
79. Kellogg M.K. Tikhonova E.B. Karamyshev A.L. Signal Recognition Particle in Human Diseases Front. Genet. 2022 13 898083 10.3389/fgene.2022.898083 35754847 PMC9214365
80. Mariampillai K. Granger B. Amelin D. Guiguet M. Hachulla E. Maurier F. Meyer A. Tohmé A. Charuel J.-L. Musset L. Development of a New Classification System for Idiopathic Inflammatory Myopathies Based on Clinical Manifestations and Myositis-Specific Autoantibodies JAMA Neurol. 2018 75 1528 1537 10.1001/jamaneurol.2018.2598 30208379 PMC6583199
81. Vulsteke J.B. De Langhe E. Claeys K. Dillaerts D. Poesen K. Lenaerts J. Westhovens R. Van Damme P. Blockmans D. De Haes P. Detection of myositis-specific antibodies Ann. Rheum. Dis. 2019 78 e7 10.1136/annrheumdis-2017-212915 29371203
82. Alkema W. Koenen H. Kersten B.E. Kaffa C. Dinnissen J.W.B. Damoiseaux J.G.M.C. Joosten I. Driessen-Diks S. van der Molen R.G. Vonk M.C. Autoantibody profiles in systemic sclerosis; a comparison of diagnostic tests Autoimmunity 2021 54 148 155 10.1080/08916934.2021.1907842 33818234
83. Clark K.E.N. Campochiaro C. Host L.V. Sari A. Harvey J. Denton C.P. Ong V.H. Combinations of scleroderma hallmark autoantibodies associate with distinct clinical phenotypes Sci. Rep. 2022 12 11212 10.1038/s41598-022-15062-4 35780179 PMC9250530
84. Dick T. Foocharoen C. Bannert B. E Carreira P. Caporali R.F. Smith V. Kumánovics G. O Becker M. Vanthuyne M. Simsek I. Coexistence of antitopoisomerase I and anticentromere antibodies in patients with systemic sclerosis Ann. Rheum. Dis. 2002 61 121 127 10.1136/ard.61.2.121 11796397 PMC1753997
85. Heijnen I.A. Mierau R. Bartz-Bazzanella P. Alavi M. Stoyanova-Scholz M. Kindler J. Genth E. Clinical significance of coexisting antitopoisomerase I and anticentromere antibodies in patients with systemic sclerosis: A EUSTAR group-based study Clin. Exp. Rheumatol. 2013 31 (Suppl. S76) 96 102 23101460
86. Johnson S.R. Soowamber M. Fransen J. Khanna D. Hoogen F.V.D. Baron M. Matucci-Cerinic M. Denton C. Medsger T. Carreira P. There is a need for new systemic sclerosis subset criteria. A content analytic approach Scand. J. Rheumatol. 2018 47 62 70 10.1080/03009742.2017.1299793 28990485
87. Johnson S.R. Progress in the clinical classification of systemic sclerosis Curr. Opin. Rheumatol. 2017 29 568 573 10.1097/BOR.0000000000000443 28961157
88. Avouac J. Fransen J. A Walker U. Riccieri V. Smith V. Muller C. Miniati I. Tarner I.H. Randone S.B. Cutolo M. Preliminary criteria for the very early diagnosis of systemic sclerosis: Results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group Ann. Rheum. Dis. 2011 70 476 481 10.1136/ard.2010.136929 21081523
89. Johnson S.R. Khanna D. Allanore Y. Matucci-Cerinic M. Furst D.E. Systemic Sclerosis Trial Design Moving Forward J. Scleroderma Relat. Disord. 2016 1 177 180 10.5301/jsrd.5000198 PMC5826575 29492470
90. Leclair V. Hudson M. Proudman S.M. Stevens W.M. Fritzler M.J. Wang M. Nikpour M. Baron M. Subsets in systemic sclerosis: One size does not fit all J. Scleroderma Relat. Disord. 2016 1 298 306 10.5301/jsrd.5000212
91. Johnson S.R. Hoogen F.V.D. Devakandan K. Matucci-Cerinic M. Pope J.E. Systemic sclerosis: To subset or not to subset, that is the question Eur. J. Rheumatol. 2020 7 (Suppl. S3) S222 S227 10.5152/eurjrheum.2020.19116 33164736 PMC7647684