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Objective Forced vital capacity (FVC) and carbon monoxide diffusion (DLCO) are used for systemic sclerosis-associated interstitial lung disease (SSc-ILD) screening. The study purpose was to determine the sensitivity, specificity, and negative predictive value (NPV) (proportion of true negative screening tests) of FVC and DLCO thresholds for SSc-ILD on chest high-resolution computed tomography (HRCT) scans. Methods Patients fulfilling American College of Rheumatology 2013 SSc criteria with a chest HRCT scan and pulmonary function tests (PFT) were studied. A thoracic radiologist quantified radiographic ILD. Optimal FVC and DLCO % predicted thresholds for ILD were identified using receiver operating characteristic curves. The FVC and DLCO combinations with greatest sensitivity and specificity were also determined. Sub-analysis was performed in patients with positive Scl-70 autoantibodies. Results 265 patients were studied. Of 188 (71%) with radiographic ILD, 59 out of 188 (31%) had “normal” FVC (≥80% predicted), and 65 out of 151 (43%) had “normal” DLCO (≥60% predicted). FVC <80% (sensitivity 0.69, specificity 0.74), and DLCO <62% (sensitivity 0.60, specificity 0.70) were optimal thresholds for radiographic SSc-ILD. All FVC and DLCO threshold combinations evaluated had NPV <0.70. The NPV for radiographic ILD for FVC <80% was lower in patients with positive Scl-70 autoantibody (NPV=0.05) compared to negative Scl-70 autoantibody (NPV=0.57). Conclusions Radiographic ILD is prevalent in SSc despite “normal” PFTs. No % predicted FVC or DLCO threshold combinations yielded high NPV for SSc-ILD screening. “Normal” FVC and DLCO in SSc patients, especially those with positive Scl-70 autoantibodies, should not obviate consideration of HRCT for ILD evaluation.

ObjectiveWe sought to determine histologic and gene expression features of clinical improvement in early diffuse cutaneous systemic sclerosis (dcSSc; scleroderma).MethodsFifty-eight forearm biopsies were evaluated from 26 individuals with dcSSc in two clinical trials. Histologic/immunophenotypic assessments of global severity, alpha-smooth muscle actin (aSMA), CD34, collagen, inflammatory infiltrate, follicles and thickness were compared with gene expression and clinical data. Support vector machine learning was performed using scleroderma gene expression subset (normal-like, fibroproliferative, inflammatory) as classifiers and histology scores as inputs. Comparison of w-vector mean absolute weights was used to identify histologic features most predictive of gene expression subset. We then tested for differential gene expression according to histologic severity and compared those with clinical improvement (according to the Combined Response Index in Systemic Sclerosis).ResultsaSMA was highest and CD34 lowest in samples with highest local Modified Rodnan Skin Score. CD34 and aSMA changed significantly from baseline to 52 weeks in clinical improvers. CD34 and aSMA were the strongest predictors of gene expression subset, with highest CD34 staining in the normal-like subset (p<0.001) and highest aSMA staining in the inflammatory subset (p=0.016). Analysis of gene expression according to CD34 and aSMA binarised scores identified a 47-gene fibroblast polarisation signature that decreases over time only in improvers (vs non-improvers). Pathway analysis of these genes identified gene expression signatures of inflammatory fibroblasts.ConclusionCD34 and aSMA stains describe distinct fibroblast polarisation states, are associated with gene expression subsets and clinical assessments, and may be useful biomarkers of clinical severity and improvement in dcSSc.

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Background: The modified Rodnan skin score is a common primary outcome measurement tool in clinical trials of systemic sclerosis (scleroderma). However, it is unknown how often physicians perform the modified Rodnan skin score in clinical practice or what precise approach is most often used when assessing each of the 17 sites included in the modified Rodnan skin score (i.e. “maximizing,” “averaging,” “representative area”). This study assessed the experiences, perceptions, training, and practices of individuals studying scleroderma with regard to modified Rodnan skin score. Methods: An invitation with an online survey link was sent electronically to 282 individuals who are part of the Scleroderma Clinical Trials Consortium. The 46-item survey included three sections: participant demographics, modified Rodnan skin score background/training, and modified Rodnan skin score assessment practices. The survey was accessible for 5 weeks (October–November 2019). Results: The response rate was 41% (116 of 282 individuals). The majority of participants perform the modified Rodnan skin score in clinical care (>99%) and practice at academic institutions (90%) in North America (41%) or Europe (40%). Nearly all participants felt that the modified Rodnan skin score is either “somewhat important” (43%) or “essential” (56%) to the care of patients with systemic sclerosis. In total, 91% of participants reported having received modified Rodnan skin score training. The majority (60%) of those who had not received training were interested in receiving modified Rodnan skin score training, and 39% of participants felt either “uncomfortable” or only “somewhat comfortable” performing the modified Rodnan skin score. The modified Rodnan skin score approach varied: 44% used “maximizing,” 28% used “averaging,” and 18% used “representative area.” Conclusion: A majority of participants feel that the modified Rodnan skin score is “essential” to the care of patients with systemic sclerosis; however, the method used to measure modified Rodnan skin score varies greatly among systemic sclerosis investigators. These results indicate a continued role of modified Rodnan skin score for care and research in systemic sclerosis, support ongoing efforts to increase opportunities for modified Rodnan skin score training, and highlight a potential need to harmonize the technical approach to measuring the modified Rodnan skin score.