Systematic Analysis of the Literature in Search of Defining Systemic Sclerosis Subsets

Abstract

Objective Systemic sclerosis (SSc) is a multisystem disease with heterogeneity in presentation and prognosis. An international collaboration to develop new SSc subset criteria is underway. Our objectives were to identify systems of SSc subset classification and synthesize novel concepts to inform development of new criteria. Methods Medline, Cochrane MEDLINE, CINAHL, EMBASE and Web of Science were searched from their inceptions to December 2019 for studies related to SSc sub-classification, limited to humans without language or sample size restrictions. Results Of 5686 citations, 102 articles reported original data on SSc subsets. Subset classification systems relied on extent of skin involvement and/or scleroderma-specific autoantibodies (n=61), nailfold capillary patterns (n=29), molecular, genomic and cellular patterns (n=12). While some systems of subset classification confer prognostic value for clinical phenotype, severity, and mortality; only subsetting by gene expression signatures in tissue samples has been associated with response to therapy. Conclusion Subsetting on extent of skin involvement remains important. Novel disease attributes including SSc-specific autoantibodies, nailfold capillary patterns and tissue gene expression signatures have been proposed as innovative means of SSc subsetting.

A Narrative Review of Pathogenetic and Histopathologic Aspects, Epidemiology, Classification Systems, and Disease Outcome Measures in Systemic Sclerosis

“…Autoantibodies Subsets Although the two subset systems by Scussel-Lonzetti et al have a fair discrimination between patients with different dominant pathogenetic features (vascular versus fibrotic), internal organ damage, and survival [67][68][69][70], it suffers from evident limitations. In common clinical practice, a certain degree of heterogeneity within these two clinical subsets can easily be observed: for example, around 1 of 4 patients with lcSSc patients has anti-topo I antibodies and, conversely, 1 of 3 anti-Topo 1 + patients has lcSSc [71].…”

“…New Approaches in SSc Subsetting Finally, as discussed in another paper in this Journal, attempts to update SSc subsetting exploiting data deriving from new tools (e.g., transcriptomics or genomics) may lead in the next future to better identification of distinct clinical trajectories, improving personalization of SSc patient care [70,74,75]. Prior to implementation of new classification schemes, these will need to be proven superior to previous subsets, reliable, feasible, and valid [76].…”

Systemic sclerosis sine scleroderma: clinical and serological features and relationship with other cutaneous subsets in a large series of patients from the national registry ‘SPRING’ of the Italian Society for Rheumatology

“…Moreover, the recognising of SSc, particularly in the early stage, is based on some cardinal signs, namely Raynaud’s phenomenon, DPS, puffy fingers, cutaneous sclerosis, sclerodactyly and/or capillaroscopic/autoantibody alterations. 2 4 …”

“…Overall, future investigations on the biological origin of the different distribution of skin fibrosis among SSc patients 29–32 may provide useful insights on the complex etiopathogenesis of the disease, likewise a novel disease sub-setting. 2 4 33 …”

“… 2 3 The two subsets have well-recognised differences with respect to disease severity and prognosis. 2 4 Furthermore, SSc sine scleroderma (ssSSc) is considered as a separate subset first described in detail by Rodnan and Fennell. 5 Its clinical presentation can be misleading, generating diagnostic uncertainties because of the lack of skin involvement, although it may have the involvement of lung, heart and gastrointestinal (GI) system.…”