Renal Manifestations in Scleroderma: Evidence for Subclinical Renal Disease as a Marker of Vasculopathy

Scleroderma is a disease characterized by immune activation, vasculopathy, fibroblast stimulation, and connective tissue fibrosis. End-organ damage occurs due to progressive tissue fibrosis and vasculopathy. Markers of incipient vasculopathy have not been well studied in scleroderma. However, reduced renal functional reserve and proteinuria are common indicators of progressive vasculopathy in diabetic and hypertensive vasculopathy. Recent studies suggest a strong association between renal involvement and outcomes in scleroderma, with a threefold increased risk of mortality from pulmonary hypertension if renal insufficiency is present. We review the types of renal involvement seen in scleroderma and the data to support the use of renal parameters including proteinuria, glomerular filtration rate, and renal vascular dynamics measured with Doppler ultrasound to identify subclinical renal insufficiency. Further studies are warranted to investigate the use of renal parameters as prognostic indicators in scleroderma

Dyspnea assessment and pulmonary hypertension in patients with systemic sclerosis: Utility of the University of California, San Diego, Shortness of Breath Questionnaire

Objective The University of California in San Diego Shortness of Breath Questionnaire (UCSD SOBQ) has been used to assess dyspnea‐related activity limitation in patients with airway and parenchymal lung disease. We sought to assess the construct validity and responsiveness of the UCSD SOBQ in systemic sclerosis (SSc; scleroderma) patients with incident pulmonary hypertension (PH) and those at high risk of developing PH. Methods We used data from 179 patients enrolled in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Registry with pre‐PH (defined by criteria on pulmonary function tests and/or echocardiogram) or definite PH with mean pulmonary artery pressure ≥25 mm Hg by right‐sided heart catheterization within 6 months of enrollment. For this analysis, we included those subjects with complete data for self‐reported measures at baseline and at 12 months. Results At baseline, the UCSD SOBQ had strong correlations in the expected direction with the disability index (DI) of the Health Assessment Questionnaire (HAQ) (r = 0.71, P < 0.0001), dyspnea assessment by visual analog scale (r = 0.71, P < 0.0001), and the Short Form 36 (SF‐36) health survey physical component summary (PCS) score (r = −0.77, P < 0.0001), as well as a moderate correlation with the 6‐minute walk test distance (r = −0.33, P < 0.0001), Borg dyspnea score (r = 0.47, P < 0.0001), and diffusing capacity of carbon monoxide (r = −0.33, P < 0.0001). Change in the UCSD SOBQ at 12 months correlated in the expected direction with change in the HAQ DI (r = 0.54, P < 0.0001) and change in the SF‐36 PCS (r = −0.44, P < 0.0001). Multivariate analysis adjusting for age, sex, and race identified male sex as a significant predictor of death (odds ratio [OR] 7.00, 95% confidence interval [95% CI] 1.55–31.76), while the UCSD SOBQ showed a strong trend toward significance (OR 1.82, 95% CI 0.97–3.41). Conclusions The UCSD SOBQ demonstrates good construct validity and responsiveness to change in SSc patients with pulmonary vascular disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96723/1/21827_ftp.pd

Lower Extremity Ulcers in Systemic Sclerosis: Features and Response to Therapy

Nondigital lower extremity ulcers are a difficult to treat complication of scleroderma, and a significant cause of morbidity. The purpose of this study was to evaluate the prevalence of nondigital lower extremity ulcers in scleroderma and describe the associations with autoantibodies and genetic prothrombotic states. A cohort of 249 consecutive scleroderma patients seen in the Georgetown University Hosptial Division of Rheumatology was evaluated, 10 of whom had active ulcers, giving a prevalence of 4.0%. Patients with diffuse scleroderma had shorter disease duration at the time of ulcer development (mean 4.05 years ± 0.05) compared to those with limited disease (mean 22.83 years ± 5.612, P value .0078). Ulcers were bilateral in 70%. In the 10 patients with ulcers, antiphospholipid antibodies were positive in 50%, and genetic prothrombotic screen was positive in 70% which is higher than expected based on prevalence reports from the general scleroderma population. Of patients with biopsy specimens available (n = 5), fibrin occlusive vasculopathy was seen in 100%, and all of these patients had either positive antiphospholipid antibody screen, or positive genetic prothrombotic profile. We recommend screening scleroderma patients with lower extremity ulcers for the presence of anti-phospholipid antibodies and genetic prothrombotic states

Clinical and serological features of systemic sclerosis in a multicenter African American cohort: Analysis of the genome research in African American scleroderma patients clinical database.

Racial differences exist in the severity of systemic sclerosis (SSc). To enhance our knowledge about SSc in African Americans, we established a comprehensive clinical database from the largest multicenter cohort of African American SSc patients assembled to date (the Genome Research in African American Scleroderma Patients (GRASP) cohort).African American SSc patients were enrolled retrospectively and prospectively over a 30-year period (1987-2016), from 18 academic centers throughout the United States. The cross-sectional prevalence of sociodemographic, clinical, and serological features was evaluated. Factors associated with clinically significant manifestations of SSc were assessed using multivariate logistic regression analyses.The study population included a total of 1009 African American SSc patients, comprised of 84% women. In total, 945 (94%) patients met the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for SSc, with the remaining 64 (6%) meeting the 1980 ACR or CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) criteria. While 43% were actively employed, 33% required disability support. The majority (57%) had the more severe diffuse subtype and a young age at symptom onset (39.1 ± 13.7 years), in marked contrast to that reported in cohorts of predominantly European ancestry. Also, 1 in 10 patients had a severe Medsger cardiac score of 4. Pulmonary fibrosis evident on computed tomography (CT) chest was present in 43% of patients and was significantly associated with anti-topoisomerase I positivity. 38% of patients with CT evidence of pulmonary fibrosis had a severe restrictive ventilator defect, forced vital capacity (FVC) ≤50% predicted. A significant association was noted between longer disease duration and higher odds of pulmonary hypertension, telangiectasia, and calcinosis. The prevalence of potentially fatal scleroderma renal crisis was 7%, 3.5 times higher than the 2% prevalence reported in the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) cohort.Our study emphasizes the unique and severe disease burden of SSc in African Americans compared to those of European ancestry

Racial Disparities in Systemic Sclerosis: Short- and Long-Term Outcomes Among African American Participants of SLS I and II

OBJECTIVE: To evaluate short- and long-term outcomes of African American (AA) participants of Scleroderma Lung Studies (SLS) I and II. METHODS: SLS I randomized 158 participants with systemic sclerosis-interstitial lung disease (SSc-ILD) to 1 year of oral cyclophosphamide (CYC) versus placebo. SLS II randomized 142 participants with SSc-ILD to 1 year of oral CYC followed by 1 year of placebo versus 2 years of mycophenolate (MMF). Joint models compared the course of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) between AA and non-AA, and Cox proportional hazard models assessed long-term morbidity and mortality outcomes. RESULTS: In SLS I, there was no difference in the course of the FVC or DLCO between AA and non-AA in either treatment arm. In SLS II, AA had an improved course of the FVC compared with non-AA in the CYC arm; in the MMF arm, there was no difference in FVC course. There was no difference in DLCO course in either arm. Time to death and respiratory failure were similar for AA and non-AA in SLS I. There was a trend for improved survival and time to respiratory failure in AA compared with non-AA in SLS II. AA race was not independently associated with mortality in the SLS I or II in the Cox models. CONCLUSION: Data from two randomized controlled trials demonstrated that AA patients with SSc-ILD have similar morbidity and mortality outcomes compared with non-AA patients. These findings contrast with the racial disparities described in prior observational studies and warrant further investigation

Registries in systemic sclerosis: a worldwide experience

SSc is a multisystem disease characterized by an unpredictable course, high mortality and resistance to therapy. The complexity and severity of SSc is a growing burden on the health-care systems. As a result, researchers are seeking new therapeutic strategies for effectively managing these patients. Disease registries are used to support care management efforts for groups of patients with chronic diseases and are meaningful to capture and track key patient information to assist the physicians in managing patients. For these reasons, SSc surveys, research associations and consortiums are pivotal to conduct ongoing research and data collection to enhance disease knowledge and support research projects. Currently, there are several national SSc registries in the UK, Germany, USA, Canada, Brazil and Australia. There is also an international registry established by the European League Against Rheumatism scleroderma trial and research (EUSTAR) called minimal essential data set (MEDS) Online, which collects data from over 8000 patients from 92 centres worldwide, including 21 European centres and 9 centres outside Europe. By collecting, analysing and disseminating data on disease progression and patient responses to long-term disease management strategies, registries help to improve understanding of the disease and keep medical professionals up to date on the latest advance

Acute Kidney Injury in Patients with Systemic Sclerosis Participating in Hematopoietic Cell Transplantation Trials in the United States

Recipients of hematopoietic cell transplantation may be at risk for developing acute kidney injury (AKI), and this risk may be increased in patients who undergo transplantation for severe systemic sclerosis (SSc) due to underlying scleroderma renal disease. AKI after transplantation can increase treatment-related mortality. To better define these risks, we analyzed 91 patients with SSc who were enrolled in 3 clinical trials in the United States of autologous or allogeneic hematopoietic cell transplantation (HCT). Eleven (12%) of the 91 patients with SSc in these studies (8 undergoing autologous HCT, 1 undergoing allogeneic HCT, 1 pretransplantation, 1 given i.v. cyclophosphamide on a transplantation trial) experienced AKI, of whom 8 required dialysis and/or therapeutic plasma exchange. AKI injury in the 9 HCT recipients developed a median of 35 days (range, 0-90 days) after transplantation. Ten of 11 patients with AKI received angiotensin-converting enzyme inhibitor (ACE-I) therapy. The etiology of AKI was attributed to scleroderma renal crisis in 6 patients (including 2 with normotensive renal crisis), to AKI of uncertain etiology in 2 patients, and to AKI superimposed on scleroderma kidney disease in 3 patients. Eight of the 11 patients died, one each because of progression of SSc, multiorgan failure, gastrointestinal and pulmonary bleeding, pericardial tamponade and pulmonary complications, diffuse alveolar hemorrhage, pulmonary embolism, graft-versus-host disease, and malignancy. Limiting nephrotoxins, cautious use of corticosteroids, renal shielding during total body irradiation, strict control of blood pressure, and aggressive use of ACE-Is may be of importance in preventing renal complications after HCT for SSc

Performance Characteristics of Pulmonary Function Tests for the Detection of Interstitial Lung Disease in Adults With Early Diffuse Cutaneous Systemic Sclerosis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163424/2/art41415.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163424/1/art41415_am.pd

Does hand involvement in systemic sclerosis limit completion of patient-reported outcome measures?

The objective of this analysis is to examine whether the severity of systemic sclerosis (SSc)-hand involvement influences patient-reported outcome measure (PROM) completion rate in a US cohort of early disease. Participants included SSc patients with less than 5 years disease duration consented and enrolled in the Collaborative, National, Quality, and Efficacy Registry (CONQUER) between June 2018 and December 2019. Participants\u27 socio-demographics, hand clinical features (severe modified Rodnan skin score, presence of small joint contractures, acro-osteolysis, calcinosis, and digital ulcers), and completion rates of seven PROMs including a Resource Use Questionnaire were analyzed. Cohort characteristics and baseline PROM completion were evaluated. Multivariable logistic regression assessed the relationship between hand limitations and PROM incompletion at several time points using generalized estimating equations. At the time of data lock, 339 CONQUER subjects had a total of 600 visits available for analysis. Calcinosis (odds ratio [OR] 6.35, confidence interval [CI] 2.41-16.73 and acro-osteolysis OR 3.88 (1.57-9.55) were significantly associated with incomplete PROM. The Resource Use Questionnaire was the PROM most commonly not completed. Increasing age was correlated with resource use questionnaire incompletion rate. Acro-osteolysis and calcinosis were associated with lower PROM completion rates in a US SSc cohort, independent of the length of the questionnaires or the modality of administration (electronic or paper). Resource Use Questionnaires are important for understanding the economic impact and burden of chronic disease; however, in this study, it had lower completion rates than PROMs devoted to clinical variables. Key points •Multiple strategies are needed to ensure optimal completion of PROM in longitudinal cohort studies. Even if patients request electronic surveys, we have found it is important to follow up incomplete surveys with paper forms provided at the time of a clinical visit. •The Resource Utilization Questionnaire was lengthy and prone to non-completion in the younger population. •Acro-osteolysis and calcinosis were associated with reduced PROM completion rates