Systemic Sclerosis-Specific Antibodies: Novel and Classical Biomarkers

Abstract

Disease-specific autoantibodies are considered the most important biomarkers for systemic sclerosis (SSc), due to their ability to stratify patients with different severity and prognosis. Anti-nuclear antibodies (ANA), occurring in subjects with isolated Raynuad’s phenomenon, are considered the strongest independent predictors of definite SSc and digital microvascular damage, as observed by nailfold videocapillaroscopy. ANA are present in more than 90% of SSc, but ANA negativity does not exclude SSc diagnosis: a little rate of SSc ANA negative exists and shows a distinct subtype of disease, with less vasculopathy, but more frequent lower gastrointestinal involvement and severe disease course. Anti-centromere, anti-Th/To, and anti-Topoisomerase I antibodies could be considered as classical biomarkers, covering about 60% of SSc and defining patients with well-described cardio-pulmonary complications. In particular, anti-Topoisomerase I represent a risk factor for development of diffuse cutaneous involvement and digital ulcers in the first 3 years of disease, as well as severe interstitial lung disease (ILD). Anti-RNA polymerase III is a biomarker with new clinical implications: very rapid skin thickness progression, gastric antral vascular ectasia, the occurrence of synchronous cancers, and possible association with silicone breast implants rupture. Moreover, novel SSc specific autoantibodies have been globally described in about 10% of “seronegative” SSc patients: anti-elF2B, anti-RuvBL1/2 complex, anti-U11/U12 RNP, and anti-BICD2 depict specific SSc subtypes with severe organ complications. Many autoantibodies could be considered markers of overlap syndromes, including SSc. Anti-Ku are found in 2–7% of SSc, strictly defining the PM/SSc overlap. They are associated with synovitis, joint contractures, myositis, and negatively associated with vascular manifestation of disease. Anti-U3RNP are associated with a well-defined clinical phenotype: Afro-Caribbean male patients, younger at diagnosis, and higher risk of pulmonary hypertension and gastrointestinal involvement. Anti-PM/Scl define SSc patients with high frequency of ILD, calcinosis, dermatomyositis skin changes, and severe myositis. The accurate detection of autoantibodies SSc specific and associated with overlap syndromes is crucial for patients’ stratification. ANA should be correctly identified using indirect immunofluorescent assay and a standardized way of patterns’ interpretation. The gold-standard technique for autoantibodies’ identification in SSc is still considered immunoprecipitation, for its high sensitivity and specificity, but other assays have been widely used in routine practice. The identification of SSc autoantibodies with high diagnostic specificity and high predictive value is mandatory for early diagnosis, a specific follow-up and the possible definition of the best therapy for every SSc subsets. In addition, the validation of novel autoantibodies is mandatory in wider cohorts in order to restrict the gap of so-called seronegative SSc patients.

Autoantibodies as Biomarker and Therapeutic Target in Systemic Sclerosis

“…However, this technique is insufficient to identify specific ANAs except for anti-centromere antibodies. Therefore, additional techniques such as ELISA, immunodiffusion or Western immunoblotting can be used to determine the patients’ individual specific antigenic targets [ 71 ].…”

“…To further explain clinical differences of ANA subspecificities, Clark et al performed a transcriptional and proteomic analysis of blood and skin of SSc patients with anti-topoisomerase I and anti-RNA polymerase III antibody specificities, revealing pathogenetic differences between ANA-based subgroups [ 78 ]. For the association of SSc-specific ANAs with corresponding clinical phenotypes, we refer to recently published reviews, e.g., by Cavazzana et al [ 71 ] or Stochmal et al [ 79 ]. In addition, recently, further ANAs were identified in subsets of SSc patients.…”

Comprehensive Autoantibody Profiles in Systemic Sclerosis: Clinical Cluster Analysis

“…103,104 For clinical practice, simple and cost-efficient methods such as ELISA and immunoblotting have become established. 105 In our study we used both methods for the determination of ACA and Topo-1 and could show a good agreement for the EUROLINE blot compared to ELISA. However, it should be noted that both methods are based on similar principles and thus share common sources of error, such as non-specific binding and cross-reactivity.…”

“…However, it should be noted that both methods are based on similar principles and thus share common sources of error, such as non-specific binding and cross-reactivity. 42,105 Furthermore, it has to be considered that the other antibodies we determined and on which our cluster analysis is based were only determined with a single technique. Mierau et al analysed sera of 863 SSc patients using different methods including IIF, a comparable line immunoassay as we did, immunoprecipitation and immunodiffusion.…”

Comprehensive autoantibody profiles in systemic sclerosis: Clinical cluster analysis

“…For the determination of antibodies in SSc, different methods exist, each of which has strengths and weaknesses ( 106 , 107 ). For clinical practice, simple and cost-efficient methods such as ELISA and immunoblotting have become established ( 108 ). In our study we used both methods for the determination of ACA and Topo-1 and could show a good agreement for the EUROLINE blot compared to ELISA.…”