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

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, the Cumulative Index to Nursing and Allied Health Literature, EMBASE, and Web of Science were searched from their inceptions to December 2019 for studies related to SSc subclassification, limited to humans and without language or sample size restrictions. Results. Of 5686 citations, 102 studies reported original data on SSc subsets. Subset classification systems relied on extent of skin involvement and/or SSc-specific autoantibodies (n = 61), nailfold capillary patterns (n = 29), and 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.

Systemic sclerosis (SSc) is a multisystem autoimmune rheumatic disease characterized by microvascular injury and accumulation of collagen in skin and other organs, such as the musculoskeletal system, lungs, kidneys, and gastrointestinal (GI) tract. 1,2,3,4,5,6SSc is associated with poorer patient outcomes and lower quality of life when compared to other rheumatic diseases. 7The 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for SSc include skin thickening, fingertip lesions, abnormal nailfold capillaries, and the presence of SSc-related autoantibodies, but do not differentiate subsets of patients with SSc. 8 Subclassification of SSc into a number of pathogenetically homogenous subsets with similar clinical manifestations and outcomes would help segregate clearly between prognostically distinct disease subgroups.Despite the complex multiorgan nature of SSc, the subsets are frequently defined as being limited cutaneous (lcSSc) or diffuse cutaneous (dcSSc), based on the location of skin involvement. 9This classification system gives insight into disease progression; however, within lcSSc and dcSSc, the course of disease is highly variable between patients. 10,11With a more modern perspective, our understanding of SSc subsets is changing.A combination of multisystem involvement, antibody profiling, genetic markers, and differences in proteomics may play a role in prognosis and treatment options. 12,13,14,15,16Further defining subsets of patients with SSc may help to prognosticate, especially in early disease. 17 international collaboration to develop new criteria to subset SSc is underway. 18Current perceptions around SSc subset criteria were identified by leading international experts.In a survey of 30 SSc experts from 13 countries, 90% of experts use > 2 subsets for classifying and treating their patients. 19Concepts such as progression rates and likely organ involvement are considered for subsetting patients with SSc informally in clinical practice.
There is a need for criteria to identify subsets of patients with SSc for recruitment into clinical trials of novel therapeutic agents, to inform management, and for prognosis in clinical care.Previous attempts to outline SSc subset classification criteria have relied mainly on clinical manifestations. 20However, in recent years, novel disease attributes including autoantibody profiles, nailfold capillary patterns, and gene expression signatures have been proposed as means of subsetting.The objectives of this study were to identify

Search results.
Our literature review identified 5686 citations, of which 5584 were excluded because they were not relevant (conditions other than SSc, no classification system proposed), they had insufficient data, the data were not original, and/or they did not involve humans.The remaining 102 studies reported schema to subset patients with SSc (Figure 1).
The diffuse vs limited SSc criteria of LeRoy, et al 9 is the most commonly used system of SSc classification.The differences in development of visceral (renal and myocardial) disease and survival were shown for the subsets. 9,11,25,26The system has a good discriminative value to identify the groups of patients with different dominant features (vascular vs fibrotic), internal organ damage, and outcome.It enables identification of patients with early SSc with poor prognosis who will need close monitoring and facilitates the comparison of more homogenous groups of patients in epidemiological studies and clinical trials.The LeRoy 1988 classification system 9 has the advantage of comprising only 2 groups and requires criteria other than cutaneous involvement.To classify as diffuse SSc (dSSc), the prerequisites are the onset of Raynaud phenomenon (RP) within 1 year of the onset of skin involvement, early and significant visceral involvement, and the absence of anticentromere antibodies (ACA).When using these strict LeRoy criteria, dSSc represents only a small portion (8.5%) of the total group with definite SSc. 23Two SSc-specific autoantibodies were included in the original LeRoy criteria: antitopoisomerase I antibodies (ATA) and ACA.
Acknowledging the important role of autoantibodies and capillary abnormalities, LeRoy updated the classification in 2001, proposing 4 subsets: limited SSc (lSSc), lcSSc, dcSSc, and diffuse fasciitis with eosinophilia.The classification includes lSSc as RP only in association with serological and/or capillary abnormalities. 32Considering that SSc is a multistage multiorgan disorder, lSSc is likely an early stage of disease and corresponds to very early SSc in the classification of Avouac, et al. 28 Others have proposed 3 subset systems based on the extent of cutaneous involvement within the first year of presentation: type I digital (finger or toe skin involvement), type II intermediate (skin involvement proximal to metacarpophalangeal [MCP] joints, but excluding trunk), and type III diffuse (truncal sclerosis). 10,24,29,33The latter type was characterized by male predominance, shorter RP before skin changes, and worse prognosis. 11The clinical distinctiveness of the types was confirmed by difference in autoantibody profile: ACA was found more frequently in type I, while ATA was more frequent in intermediate SSc (iSSc) and dSSc.In the study, the authors included only SSc patients with disease duration ≤ 2 years after the onset of skin lesions, and none of the patients had received any treatment that could potentially affect skin sclerosis prior to the enrollment.That ruled out the possibility that the iSSc group consisted of patients with SSc that would evolve into dSSc later or who originally had dSSc with skin regression under the treatment.Compared to the 2-subset LeRoy system, this classification better reflects the clinical heterogeneity of disease and identifies the subgroups with milder or more severe clinical prognostic evolution.
The simplicity of this 3-subset classification, which is based on clinical examination of skin only and does not require special equipment or tests, makes it highly reproducible and suitable for clinical care and research studies.Notably, this classification system includes a time determinant reflective of the pace of disease, and thus has a prognostic value.Barnett, et al 10 emphasized the importance of assessing the extent of skin involvement within the first year of presentation to place a patient into a specific type.Indeed, type I and II patients had a better prognosis in terms of life expectancy compared to type III.However, only slight difference in survival was found between patients with iSSc and those with lSSc.
Patients with iSSc were found to have variable clinical features and represented a serologically heterogeneous group.It raises the question of iSSc as a distinct variant.Some authors suggested that further subdivision of iSSc might be necessary to identify the subsets with particular patterns of internal organ damage and outcome.Scussel-Lonzetti, et al 25 divided iSSc into "above elbow" and "below elbow" groups but found them similar with respect to internal organ involvement, mortality, and autoantibody profile.Although the authors supported the concept of an iSSc subset, differentiation was shown only between the LeRoy subsets ("normal + limited" vs "intermediate + diffuse") in terms of heart involvement, disease activity (elevated erythrocyte sedimentation rate [ESR], anemia), and pulmonary fibrosis.The most significant difference in survival rates was found between lSSc and dSSc, whereas the difference between other subsets was absent (lSSc vs iSSc, P = 0.2) or very low (iSSc vs dSSc, P = 0.03).ATA positivity was similar between iSSc and dSSc while ACA frequencies gradually decreased from lSSc through iSSc to dSSc (50%, 34%, and 3.4%, respectively).Supporting the LeRoy system, the skin involvement proximal to MCP joints was one of the strong predictors of mortality.In line with those findings, Vayssairat, et al 23 showed the advantages of LeRoy subset system and disutility of adding iSSc as a subset.When patients with proximal skin thickening were divided into intermediate and truncal subsets, no difference in severity score was found between them.
The patients with calcinosis, RP, esophageal involvement, sclerodactyly, telangiectasia (CREST) syndrome, suspected secondary RP, and/or visceral SSc without skin involvement were not acknowledged in the aforementioned 2 classification systems. 9,10The recently developed immunoblotting technique to detect SSc-related autoantibodies and nailfold capillary microscopy allows the detection of these probable connective tissue diseases.Expanding the subsets, Maricq, et al 22 added undifferentiated connective tissue disorder with SSc features, SSc sine scleroderma, and CREST.This classification allows the inclusion of patients who are in earlier stages of their disease.
Boonstra, et al 27 identified 4 clinical subgroups by hierarchical clustering using skin, musculoskeletal, cardiac, pulmonary, and GI manifestations; demographics; and risk assessment using follow-up data.Subgrouping patients allowed the prediction of severity and mortality with 2 subgroups showing higher-than-average 5-year mortality rates: subgroup 1 (male predominance, dcSSc, higher modified Rodnan skin score [mRSS], scleroderma renal crisis (SRC), ATA, less frequent interstitial lung disease [ILD]); and subgroup 2 (female and non-White predominance, more frequent pulmonary arterial hypertension [PAH], gastric antral vascular ectasia [GAVE], ILD, and lower diffusing lung capacity for carbon monoxide [DLCO] and forced vital capacity [FVC]).Low-risk clusters (subgroups 3 and 4) included patients with lcSSc who were predominantly female, had more frequent GI manifestations (dysphagia, diarrhea, constipation) for both subgroups, as well as peripheral vascular involvement (digital ulcers), ACA, and White predominance for subgroup 3, and less frequent ILD, FVC, and DLCO for subgroup 4. Three subgroups (1,  3, and 4) were similar to the clusters (6, 3, and 1, respectively) in another subclassification system developed by Sobanski, et al as a European Scleroderma Trials and Research Group clustering initiative. 37However, 2 main clusters, A and B, in the latter study strongly support the LeRoy 2001 32 subclassification into dcSSc and lcSSc.

SSc subsets based on molecular gene expression profiling.
Another approach to classifying patients with SSc into subsets is molecular phenotyping identified through gene expression profiling in tissue samples.41][42][43][44][45]49,121 The intrinsic molecular subsets are consistent for each patient, as well as across the different skin biopsy sites, regardless of clinically affected or unaffected status. 38,122The subsets are also consistent across the organ systems 38,39,42,122 ; however, highly lung-specific innate immune and cell proliferation processes were shown within the immune-fibrotic axis, suggesting that there are gene pairs that are more likely to interact in one tissue than the other (Table 2). 123c subsets according to SSc-related autoantibodies.
The classification system according to serum antibodies is based on the findings of mutually exclusive, SSc-specific autoantibodies that did not change during the course of disease.The autoantibody subsets are distinguished by patterns of cutaneous involvement, specific clinical features, and prognosis (Table 3).SSc-specific autoantibodies were found to be stronger predictors of disease outcome and organ involvement than the extent of skin involvement. 27The subset of patients with SSc positive for ACA represents a clinically homogenous group with distinct clinical features and seems to have a better prognosis: less severity; less frequent ILD, SRC, inflammatory arthritis, and inflammatory myositis; and patients had lower rates of GI tract involvement, finger ulcers, digital tuft resorption, or finger contractions.The patients are also older at disease onset, predominantly female, and more likely to have limited disease, lower skin scores, telangiectasia and pulmonary hypertension. 10,21,29,51-57,59,61-63, 65,69-71,73,74,84,86,89,124ACA status was found to be predictive of the extent of skin involvement over time. 59Patients with limited disease who were ACA-negative at baseline were more likely to progress to diffuse disease.ACAnegative patients also had a greater extent of cutaneous involvement, worse survival, and more severe internal organ involvement. 29,65other study supported subdivision of lcSSc into 2 serological subtypes, Th/To-positive and ACA-positive, with different internal organ involvement and outcome. 50Compared to the ACA-positive patients, Th/To-positive patients were younger at disease onset and predominantly male, with less PAH development, but more ILD (38% vs 4.5%).The highest mortality was found in ATA+ and ATA+/ACA-subgroups, while ACA+/ ATAand Pm/Scl+/RNA polymerase antibody (RNAP)-negative patients were classified as low risk. 26Some patients were not within described serological subsets; for example, ACA was commonly found in association with mild skin involvement, but 9% of dcSSc patients with truncal involvement were positive for ACA. 10 Caetano, et al described those patients who had a more insidious onset of skin and major organ involvement, a lower incidence of ILD and SRC, and better survival than expected for dcSSc as a distinct clinical subtype (dcSSc ACA+). 70Thus, further subgrouping within each autoantibody profile may be promising from a clinical point of view.Indeed, 2 subgroups of anti-CENPA can explain variable clinical manifestations in an ACA-positive subset. 87ubgrouping among patients with SSc positive for anti-RPC155 antibodies (RNAP III large subunit, 155 kDa) revealed that anti-RPA194 was associated with a lower cancer risk and less severe GI disease, while anti-RNAP I/II/III was associated with SRC. 75Therefore, different autoantibody combinations have utility as tools for organ involvement and cancer risk stratification in SSc.
Patterson, et al 86 reported subgrouping RNAP III-positive patients into 2 clusters; a strongly positive cluster was associated with an increased risk of GAVE, lower risk of esophageal dysmotility, and shorter disease duration.A strong positivity for anti-RNAP III (a higher ELISA index) was associated with the development of SRC. 75Although 3 main autoantibodies (ACA, ATA, and anti-RNAP III) have strong mutually exclusive relationships, coexpression of other antibodies are relatively common. 86,90,125,126A combination of 2 SSc-related autoantibodies was revealed in one-third of patients in the study by Patterson, et al. 86 Anti-Ro52 most frequently occurred in combination with other autoantibodies, but coexpressions of ATA with anti-RNAP III (0.6%) and ACA (3%) were also found in a small proportion of patients with SSc. 86In cases with coexistence of ≥ 2 autoantibodies, the autoantibody of highest titer determined the clinical phenotype.

SSc subsets according to nailfold capillary abnormalities.
Capillary abnormalities seen on nailfold video capillaroscopy (NVC) can be used to subgroup SSc patients with different clinical manifestations and prognoses.There are 2 classification systems based on the NVC changes (Table 4).First, Maricq, et al 127 described 2 capillary patterns: "slow" and "active."Slow pattern was characterized by capillary telangiectasias and high number of extremely large (giant) capillary loops with a relatively well-preserved capillary distribution.The main feature of active pattern was moderate-toextensive capillary loss associated with considerable distortion of the nailfold capillary bed and new blood vessel formation (bushy capillaries).Associations between capillaroscopic findings and disease activity, degree of progression, and prognosis were found.SSc patients with slow pattern predominantly had slowly progressive disease (new symptoms/signs during follow-up were found only in 1/11 patients), longer RP prior to entry, and were ACA-positive, while all patients with active pattern were ACA-negative and half showed disease progression.Capillary loss (active pattern) reflected disease progression that was confirmed in other publications. 98,114Ostojic, et al 103 found that enlarged capillaries without a significant capillary loss (slow pattern) were more frequently seen in lcSSc, whereas giant capillaries (GCs) with advanced capillary loss (active pattern) occurred in dcSSc.
The Maricq NVC classification system has been further subdivided within the active pattern into "active" and "late," whereas slow pattern was renamed as "early" by Cutolo, et al. 95,128 The principal change was the interpretation of patterns as consecutive phases of progressive obliterative microangiopathy. 128Early pattern is characterized by a relatively well-preserved capillary distribution and density with a few enlarged capillaries/GCs, few capillary microhemorrhages, and no evident loss of capillaries.The following moderate loss of capillaries is a sign of the next active phase, with a mildly disturbed architecture of capillaries, frequent GCs and microhemorrhages, capillary derangement, and absent or few ramified capillaries (neoangiogenesis).The capillary changes typical for this phase (hemorrhages and GCs) are closely associated with disease activity.Sambataro, et al showed that NEMO score (cumulative number of microhemorrhages and microthrombosis) ≥ 6 was the best predictor of disease activity, followed by the GC score (number of GCs) ≥ 3. 118 The active pattern had more severe disease manifested as extensive skin involvement and greater visceral involvement (muscle, kidney), and patients were ACA-negative in comparison with the early pattern. 91In the most advanced phase of SSc microangiopathy, represented by the late NVC pattern, the disorganization of the normal capillary array is generally seen, with severe loss of capillaries and large avascular areas, irregular enlargement of the capillaries, few or absent GCs, microhemorrhages, and ramified/bushy capillaries.Normal NVC pattern is rarely seen in SSc (4-12%), nearly exclusively in the lcSSc subset. 103,129umerous studies confirmed that patients with more advanced NVC patterns had more severe disease. 91,92,93,98,103,127,129Significant capillary loss was more common in patients with lcSSc who met ACR criteria compared to those who did not. 115assifying patients with SSc according to NVC patterns may predict development of a new organ involvement within 1 year. 98,100In 2 studies, 98,100 the odds ratio to develop severe organ involvement (defined as a category 2 or higher in any of the 9 organ systems assessed according to the Medsger Disease Severity Scale, or new PAH or ILD at 18-24 months' follow-up) was stronger according to more severe NVC patterns, adjusting for disease duration, subset, and vasoactive medications.These findings were externally validated in an Italian cohort. 100Associations between certain manifestations and NVC patterns are controversial, such as reduced capillary density and PAH. 107,108Sample size was sometimes too small to detect possible associations. 104l 3 NVC patterns can be observed in both clinical disease subsets (lcSSc and dcSSc) 128 ; however, early pattern is more common in lcSSc, especially early lcSSc, 93 whereas the late pattern is more prevalent in dcSSc. 92,93Classifying patients into NVC subsets is important early in the disease course because capillary loss is a reliable indicator of rapidly progressive early disease. 25,94Shenavandeh, et al showed that late pattern in patients with early SSc was associated with severity of finger contractures and significantly reduced pulmonary function, compared to active and early patterns. 941][112][113][114]117,118,119 The ACR criteria sensitivity may be improved by adding the NVC patterns. 115,116More severe NVC patterns (active and late) occurred in patients seropositive for ATA and anti-RNAP III, and negative for ACA. 93,95,117,119NA-negative 99 and ACA-positive 94 patients had the most favorable early pattern.However, SSc-related autoantibodies are not directly linked with the development of a distinct SSc NVC pattern (Table 4 and Table 5). 129he limitations included small proportions of patients with each NVC pattern (especially early pattern), resulting in limited power to detect statistically significant differences.Some outcomes were omitted from the analysis (i.e., GI involvement and SRC), while others might have been interrelated (i.e., abnormalities in the cardiac measures might be secondary to pulmonary involvement, rather than present as primary cardiac involvement).Further, follow-up duration in the prospective studies varied and was relatively short.Definitions of organ involvement also varied between the studies, which made the comparison of the results difficult.

DISCUSSION
SSc subset classification is a rapidly evolving field.Our systematic review highlights both the continued importance of skin involvement and the novel role of SSc-specific antibodies, abnormal nailfold capillary patterns, and molecular profiling in assessing patients to determine a subset.
The dcSSc subset comprises patients with rapidly progressive disease who require more aggressive treatment.However, disease progression assessed as severity-duration ratio (early significant visceral and skin involvement) suggests disease activity only in early dcSSc. 23,130,131In later stages of disease, patients classified as rapid progressors in the beginning may still have a high disease severity due to the accumulated significant damage, but low disease activity as a result of treatment or spontaneous remission.Some patients with SSc first develop severe skin involvement and/or visceral disease late in the disease course.Thus, the limited/diffuse system loses its predictive value in more advanced disease and should be supplemented with a necessary determination of disease activity and severity when it comes to choosing treatment.With the recent advances in antibody detection, some novel SSc-specific autoantibodies could be added to SSc subset classification autoantibody profiling to the skin involvement while determining a subset.
Based on gene expression profiling, patients with lcSSc can be assigned to the limited, inflammatory, or normal-like subsets, whereas fibroproliferative subset can be seen in patients with dcSSc.The molecular subsets seem to be a universal feature of SSc endtarget organ pathology, not affected significantly by heterogeneity of skin involvement within a patient and/or fibroblast heterogeneity in tissues. 38,39,122The molecular intrinsic subset assignment could represent a valuable approach for matching patients with SSc to appropriate therapies.Molecular phenotyping may aid personalized medicine by identifying therapies with higher potential for success in each individual patient, as well as to select patients with SSc who will improve naturally as part of their disease course. 47me limitations of subgrouping by molecular phenotyping include the relatively small sample sizes of clinical trials due to the rarity of disease itself, specific inclusion criteria that misrepresents the full spectrum of SSc, lack of controls, and differences in methods of transcript quantification and in the exact list of genes between studies.Moreover, not all therapy-or disease-relevant genes are regulated at the mRNA level.The use of molecular subsetting in clinical practice for individual patients is limited, as paired skin samples from each individual are often not available, analyses are not standardized, and large numbers of samples in a dataset are needed to identify the molecular subset with accuracy.Recently, supervised machine learning algorithms have been developed and may be successfully used to assign single samples to intrinsic gene expression subsets according to predefined criteria. 47The method utilizes a multinomial elastic net classifier and an optimized set of genes.Classifier accuracy in that study was proved using concordance of samples (83.3%) reporting Cohen κ coefficient (0.7391), and was externally validated.Further efforts are needed to explore molecular heterogeneity and intrinsic subsets in other tissues and particularly in peripheral blood, given its accessibility.
Attempts to identify SSc subsets considering SSc-specific autoantibodies have faced a variety of challenges.Boonstra, et al reported that adding autoantibody status to the cluster process resulted in correct classification of patients with ILD, PAH, and SRC. 27ll high-risk patients were correctly identified by taking autoantibodies into account, but the number of patients incorrectly identified as possibly high risk increased significantly (by 66%), suggesting limited additional value of autoantibody status for clustering. 27The limitations of studies on SSc-specific autoantibodies included underestimation of the number of antigens due to the limitations of the techniques not allowing the identification of membrane proteins, or to a loss of proteins at each step, small sample size, a lack of validation groups, and/or limited generalizability (e.g., SRC is rare in Japanese patients; clinical features in each SSc-related ANA-based subgroup appear to vary among populations of different backgrounds).Feasibility is another consideration, as some autoantibodies are identified by immunoprecipitation, which is not widely used in clinical laboratories, and/or some detection kits are not commercially available.Limitations of classification systems developed by cluster analysis are the exclusion of a significant number of patients due to missing data and/or loss to follow-up that affects the extrapolation of the results.Finally, there have been inconsistent definitions of variables between the studies, a lack of analysis of the potential effect of treatment regimens on survival, and the influence of disease duration on the clustering process.
In conclusion, modern methods to subset SSc include skin involvement, immunologic profile, molecular signatures, visceral involvement, and age.Classifying on the basis of skin involvement, NVC, and autoantibody profile may allow early prediction of internal organ involvement.Molecular subsetting may identify those who are likely to respond to therapy.Longitudinal prospective studies to track subsets are needed to provide insight into disease trajectory, assess their predictive value, and confirm a possible transition between subsets and evolution under treatment.• Diffuse proliferation: higher mRSS, all dcSSc, longer disease duration compared to patients with dcSSc in the inflammatory and normal-like groups; increased number of proliferating cells in the epidermis.
• Inflammatory: both lcSSc and dcSSc; increased T cell infiltration in the dermis.
• Normal-like: both dcSSc and lcSSc.• The gene-based subsets are reproducible, inherent, stable over time, and independent of disease duration.The intensity of the signature is associated with changes in disease duration and mRSS (i.e., high expression fibroproliferative subset associated with longer disease duration and higher mRSS; low expression inflammatory subset associated with higher mRSS).
• Identified the core sets of genes consistently associated with the intrinsic subsets, and created a gene-gene interaction network across the intrinsic subsets.• 4/5 improvers mapped to the inflammatory intrinsic subset showed decreased gene expression in inflammatory pathways over 24 weeks.One improver had normal-like signature (spontaneous improver?).
Gordon 2018 44 USA 21 15 patients were assigned to either an inflammatory or a proliferative molecular subset at baseline • Inflammatory, proliferative, normal-like.
• Molecular subset at baseline was not associated with clinical improvement in the belimumab arm, the placebo arm, or the pooled treatment arms.
• An overall reduction in inflammatory gene expression and movement toward the normal-like subset was associated with improvement in mRSS; 8/10 improvers were assigned to a normal-like molecular subset posttreatment.

USA 16
Patients from multiple clinical trials Immune and fibrotic signatures.High "inflammatory" signatures represented an active disease state.Epithelialmesenchymal transition was significantly decreased in improvers from all trials.Different immunomodulatory treatments modulate distinct functional processes (i.e., ABA had higher scores for vascular-and collagen-related modules, while MMF had higher scores for proliferation and type I interferon modules). Frost This work was supported by a grant from the Scleroderma Foundation and the World Scleroderma Foundation.SRJ is supported by a Canadian Institutes of Health Research New Investigator Award and the Gurmej Kaur Dhanda Scleroderma Research Award.DK was funded by the National Institutes of Health/ National Institute of Arthritis and Musculoskeletal and Skin Diseases grant 5K24AR063120-07.

Figure 1 .
Figure 1.Flow diagram of search results.CINAHL: Cumulative Index to Nursing and Allied Health Literature.

Table 1 .
Summary of clinical SSc subsets.Group 3 and/or Group 4 and/or Group 5 and abdomen.Three subsets were designated: "limited" skin involvement of fingers, face, neck, axillae; "intermediate" skin involvement proximal to fingers; "diffuse" truncal skin involvement.

Table 3 .
Associations between SSc-related autoantibodies and clinical SSc manifestations.Strengthening the Reporting of Observational Studies inEpidemiology checklist.

Table 5 .
Association between particular capillary abnormalities and clinical manifestations in patients with SSc.

of Patients Classification Associations With Clinical Picture, SSc-related Autoantibodies, or Outcome
Greater apex, loop, and limb widths in SSc compared to controls and patients with R A• Shorter loop length and fewer capillaries, longer interpeak capillary distance, greater degree of variation in interpeak distances in SSc, compared to controls• No association with clinical manifestations and serological data Extreme capillary loss: longer disease duration • No significant correlation found between the presence or severity of capillary enlargement (and capillary loss) and the extent/ no. of organ involvement• Telangiectasias correlated with the presence and severity of nailfold capillary enlargement: all patients with extremely enlarged capillary loops had telangiectasias

of Patients Classification Associations With Clinical Picture, SSc-related Autoantibodies, or Outcome
Low capillary density: SSc-related PAH compared with those without PAH, while loop dimensions were equal • Capillary density: severity of PAH in both SSc-related and idiopathic PAH Lee method, (3) no. of enlarged loops, and (4) no. of giant capillary loops Higher vascular deletion: mRSS, ATA+, finger pad lesions, ≥ 3 internal organs involved, dcSSc, compared to lcSSc, SSc sine scleroderma, and overlap syndrome 4%), sensitivity (92.98%) at the cut-off value of 2.96, and reproducibility (κ statistic measure of interrater agreement of 0.8514) of CSURI for the persistence and/or appearance of new DUs Altered CSURI is one of the factors associated with the appearance of DU • A prediction risk chart of the development of DUs within 6 months with 4 risk classes were built on the basis of CSURI, male sex, history of DUs, and ESR Increased number of giant capillaries: less risk to develop new DUs • Loss of capillaries within a follow-up: overall disease progression, appearance of new DUs, progression of pulmonary vascular involvement, skin fibrosis, and worsening of the Medsger severity score Severe capillary loss (grade C or D avascular areas) : lcSSc ACR+ vs the lcSSc ACR-group.• The sensitivity of ACR criteria was improved from 33.4% to 74.3% by adding grade 2 or 3 dilated capillaries, then further to 82.9% by grade C or D avascular areas, and to 88.8% with clinically visible capillary telangiectasias or absence of any dilated loops, GC loops and/or avascular areas for each digit; no scoring was done The sensitivity of the ACR criteria in lcSSc was improved from 67% to 99% by adding nailfold capillary abnormalities and clinically visible telangiectasias