Publications by authors named "Lorinda Chung"

122 Publications

Safety and Efficacy of B-Cell Depletion with Rituximab for the Treatment of Systemic Sclerosis Associated Pulmonary Arterial Hypertension: A Multi-center, Double-blind, Randomized, Placebo-controlled Trial.

Am J Respir Crit Care Med 2021 Mar 2. Epub 2021 Mar 2.

VA Palo Alto, Stanford University, Medicine, Palo Alto, California, United States.

Rationale: Systemic sclerosis-pulmonary arterial hypertension (SSc-PAH) is one of the most prevalent and deadly forms of PAH. B cells may contribute to SSc pathogenesis.

Objective: We investigated the safety and efficacy of B-cell depletion for SSc-PAH.

Methods And Measurements: In an NIH-sponsored, multi-center, double-blinded, randomized, placebo-controlled, proof-of-concept trial, 57 SSc-PAH patients on stable-dose standard medical therapy received two infusions of 1000 mg of rituximab or placebo administered two weeks apart. The primary outcome measure was the change in six-minute walk distance (6MWD) at 24 weeks. Secondary endpoints included safety and invasive hemodynamics. We applied a machine learning approach to predict drug-responsiveness.

Main Results: We randomized 57 subjects from 2010-2018. In the primary analysis, using data through week 24, the adjusted mean change in 6MWD at 24 weeks favored the treatment arm but did not reach statistical significance (23.6±11.1m vs. 0.5±9.7m, p=0.12). While a negative study, when data through week 48 were also considered, the estimated change in 6MWD at week 24 was 25.5±8.8m for rituximab and 0.4±7.4m for placebo (p=0.03). Rituximab treatment appeared to be safe and well tolerated. Low levels of rheumatoid factor (RF), IL-12, and IL-17 were sensitive and specific as favorable predictors of a rituximab response as measured by an improved 6MWD (ROC AUC 0.88-0.95).

Conclusions: B cell depletion therapy is a potentially effective and safe adjuvant treatment for SSc-PAH. Future studies in these patients can confirm whether the identified biomarkers predict rituximab-responsiveness. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT01086540.
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http://dx.doi.org/10.1164/rccm.202009-3481OCDOI Listing
March 2021

A Systematic Review and Meta-Analysis to Inform Cancer Screening Guidelines in Idiopathic Inflammatory Myopathies.

Rheumatology (Oxford) 2021 Feb 18. Epub 2021 Feb 18.

Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Objectives: To identify clinical factors associated with cancer risk in the idiopathic inflammatory myopathies (IIMs) and to systematically review the existing evidence related to cancer screening.

Methods: A systematic literature search was carried out on Medline, Embase and Scopus. Cancer risk within the IIM population (i.e. not compared to the general population) was expressed as risk ratios (RR) for binary variables and weighted mean differences (WMD) for continuous variables. Evidence relating to cancer screening practices in the IIMs were synthesised via narrative review.

Results: Sixty nine studies were included in the meta-analysis. Dermatomyositis subtype (RR 2.21), older age (WMD 11.19), male gender (RR 1.53), dysphagia (RR 2.09), cutaneous ulceration (RR 2.73), and anti-transcriptional intermediary factor-1 gamma positivity (RR 4.66) were identified as being associated with significantly increased risk of cancer. Polymyositis (RR 0.49) and clinically amyopathic dermatomyositis (RR 0.44) subtypes, Raynaud's phenomenon (RR 0.61), interstitial lung disease (RR 0.49), very high serum creatine kinase (WMD -1189.96) or lactate dehydrogenase (WMD -336.52) levels, and anti-Jo1 (RR 0.45) or anti-EJ (RR 0.17) positivity were identified as being associated with significantly reduced risk of cancer. Nine studies relating to IIM-specific cancer screening were included. Computed tomography (CT) scanning of the thorax, abdomen and pelvis appeared to be effective in identifying underlying asymptomatic cancers.

Discussion: Cancer risk factors should be evaluated in patients with IIM for risk stratification. Screening evidence is limited but CT scanning could be useful. Prospective studies and consensus guidelines are needed to establish cancer screening strategies in IIM patients.
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http://dx.doi.org/10.1093/rheumatology/keab166DOI Listing
February 2021

Long-Term Outcomes in Patients with Connective Tissue Disease-Associated Pulmonary Arterial Hypertension in the Modern Treatment Era: Meta-Analyses of Randomized, Controlled Trials and Observational Registries.

Arthritis Rheumatol 2021 Feb 3. Epub 2021 Feb 3.

University of Michigan, Ann Arbor, MI, USA.

Objective: Data on the magnitude of benefit of modern pulmonary arterial hypertension (PAH) therapies in connective tissue disease-associated PAH (CTD-PAH) are limited. We performed meta-analyses of randomized, controlled trials (RCTs) and registries to quantify this benefit (PROSPERO# CRD42020167119).

Methods: PubMed and EMBASE were searched for articles reporting data from RCTs or registries published 1/1/2000-11/25/2019. Eligibility criteria included multicenter studies with ≥30 CTD-PAH patients. RCTs had to evaluate approved PAH therapy and report long-term clinical morbidity/mortality or 6-minute walk distance. Registries had to report survival. Random effects models were used to pool data.

Results: Eleven RCTs (N=4329 n=1267 CTD-PAH) and 19 registries (N=9739; n=4008 CTD-PAH) were included. Investigational therapy produced a 36% reduction in risk of clinical morbidity/mortality events versus control (HR=0.64; 95%CI: 0.54-0.75; P<0.001) in all patients and a 36% reduction (HR=0.64; 95% CI: 0.51-0.81; P<0.001) in CTD-PAH patients. Survival was lower in CTD-PAH versus all patients (62%, 95% CI: 57%-67% versus 72%, 95% CI: 69%-75% at 3 years). Survival in CTD-PAH patients treated primarily after 2010 was higher than in those treated before (73%, 95% CI: 62%-81% versus 65%, 95% CI: 59%-71% at 3 years).

Conclusions: Modern therapy provides a similar reduction in morbidity/mortality risk in CTD-PAH and the overall PAH population. Risk of death is higher in CTD-PAH than in PAH overall, but survival has improved in the last 10 years, which may be related to increased screening and/or new treatment approaches. Early detection of PAH in patients with CTD and upfront intensive treatment are warranted.
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http://dx.doi.org/10.1002/art.41669DOI Listing
February 2021

Increased Rates of Obstetric Complications Prior to Systemic Sclerosis Diagnosis.

Arthritis Care Res (Hoboken) 2020 Dec 8. Epub 2020 Dec 8.

Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA, USA.

Objective: To investigate whether obstetric complications prior to systemic sclerosis (SSc) diagnosis are more common compared to the general obstetric population.

Methods: A case-control study was performed at Kaiser Permanente Northern California to compare prior obstetric complications in adult women who later developed SSc (cases) with women from the general obstetric population who did not develop SSc (controls; matched 10:1 by age and year of delivery) from 2007-2016. Exposures included past hypertensive disorders of pregnancy (preeclampsia, eclampsia, gestational hypertension), premature rupture of membranes (PROM), intrauterine growth restriction (IUGR), maternal infections, neonatal intensive care unit (NICU) admission, and preterm birth. Fischer's exact tests were used to compare categorical variables. Conditional logistic regression models estimated the odds ratio (OR) and corresponding 95% confidence intervals for the outcome SSc.

Results: Seventeen SSc cases and 170 non-SSc controls were identified, with median maternal age at delivery 34 years (range 23-46 years) and median time from delivery to SSc diagnosis 2 years (range 0.2-7.3 years). SSc cases were more likely to be Hispanic and Black. Prior obstetric complications appeared higher in women with an eventual SSc diagnosis compared to controls (70.6% vs. 50%), including hypertensive disorders (17.7% vs. 9.4%), PROM (11.8% vs. 4.1%), IUGR (5.9% vs 1.8%), maternal infection (29.4% vs. 14.1%), NICU admissions (23.5% vs. 7.7%), and preterm delivery (29.4% vs. 21.8%). Cases had a higher odds of delivering infants requiring NICU admission (OR=4.7, 95% CI 1.2-18.8).

Conclusions: Women who eventually develop SSc had trends towards more complicated pregnancy histories before overt diagnosis.
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http://dx.doi.org/10.1002/acr.24533DOI Listing
December 2020

Rituximab Versus Mycophenolate in the Treatment of Recalcitrant Connective Tissue Disease-Associated Interstitial Lung Disease.

ACR Open Rheumatol 2021 Jan 4;3(1):3-7. Epub 2020 Dec 4.

Stanford University, Stanford, California, United States.

Objective: Interstitial lung disease (ILD) is a major cause of morbidity and mortality in connective tissue diseases (CTDs). We aimed to assess the effect of rituximab ± mycophenolate mofetil (MMF) compared with MMF on pulmonary function and prednisone dosage in patients with CTD-related ILD (CTD-ILD).

Methods: This retrospective study included 83 patients from Stanford and Centre Hospitalier de l'Universite de Montreal. Fifteen patients received rituximab ± MMF (rituximab group), and 68 patients received MMF only (control group).

Results: Median ILD duration at the start of treatment was longer in the rituximab group at 47 months (range: 4-170) versus 6.5 months (range: 0-164) in controls. Forced vital capacity (FVC) decreased by 3.0% (range: 11%-21%) after treatment in the rituximab group, whereas it increased by 2.0% (range: 14%-25%) in the control group (p = 0.025). Diffusing capacity of carbon monoxide (DLCO) decreased by 3.0% (range: 10%-12%) after treatment in the rituximab group, whereas it increased by 4.5% (range: 30%-36%) in the control group (p = 0.046). Mixed model analysis controlling for ILD duration, baseline DLCO, systemic sclerosis, pulmonary hypertension, and prednisone use showed no significant difference in FVC or DLCO between groups at 6 months or 1 year. The average daily prednisone dose score decreased after treatment in the rituximab group, whereas it remained unchanged in the control group (p = 0.017).

Conclusion: Rituximab ± MMF did not significantly change pulmonary function compared with MMF alone, but it did result in a relative decrease in average daily prednisone dose in a population with recalcitrant CTD-ILD.
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http://dx.doi.org/10.1002/acr2.11210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811692PMC
January 2021

Efficacy and safety of nintedanib in Asian patients with systemic sclerosis-associated interstitial lung disease: Subgroup analysis of the SENSCIS trial.

Respir Investig 2021 Mar 19;59(2):252-259. Epub 2020 Nov 19.

Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan.

Background And Objective: In the SENSCIS trial in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) (mL/year) over 52 weeks by 44% in comparison with placebo, with manageable adverse events in most patients. We analyzed the efficacy and safety of nintedanib in patients of Asian race.

Methods: Patients with SSc-ILD were randomized to receive nintedanib or placebo. The outcomes over 52 weeks were analyzed in Asian versus non-Asian patients.

Results: Of the 288 patients in each treatment group, 62 (21.5%) in the nintedanib group and 81 (28.1%) in the placebo group were Asian; 90.2% of the Asian patients were enrolled in Asian countries. In the placebo group, the rate of FVC decline over 52 weeks was consistent between Asian and non-Asian patients (-99.9 and -90.6 mL/year, respectively). The effect of nintedanib on reducing the rate of FVC decline over 52 weeks was consistent between Asian (difference, 44.3 mL/year [95% CI: -32.8, 121.4]) and non-Asian patients (difference, 39.0 mL/year [95% CI: -5.1, 83.1]) (treatment-by-time-by-subgroup interaction, p = 0.91). Diarrhea was the most frequent adverse event and was reported in similar proportions of Asian and non-Asian patients in the nintedanib group (80.6% and 74.3%, respectively) and placebo group (28.4% and 32.9%, respectively).

Conclusions: In patients with SSc-ILD, nintedanib had a consistent benefit on slowing the progression of SSc-ILD in Asian and non-Asian patients, with a similar adverse event profile.

Trial Registration: ClinicalTrials.gov NCT02597933.
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http://dx.doi.org/10.1016/j.resinv.2020.10.005DOI Listing
March 2021

Chromatin accessibility landscapes of skin cells in systemic sclerosis nominate dendritic cells in disease pathogenesis.

Nat Commun 2020 11 17;11(1):5843. Epub 2020 Nov 17.

Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.

Systemic sclerosis (SSc) is a disease at the intersection of autoimmunity and fibrosis. However, the epigenetic regulation and the contributions of diverse cell types to SSc remain unclear. Here we survey, using ATAC-seq, the active DNA regulatory elements of eight types of primary cells in normal skin from healthy controls, as well as clinically affected and unaffected skin from SSc patients. We find that accessible DNA elements in skin-resident dendritic cells (DCs) exhibit the highest enrichment of SSc-associated single-nucleotide polymorphisms (SNPs) and predict the degrees of skin fibrosis in patients. DCs also have the greatest disease-associated changes in chromatin accessibility and the strongest alteration of cell-cell interactions in SSc lesions. Lastly, data from an independent cohort of patients with SSc confirm a significant increase of DCs in lesioned skin. Thus, the DCs epigenome links inherited susceptibility and clinically apparent fibrosis in SSc skin, and can be an important driver of SSc pathogenesis.
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http://dx.doi.org/10.1038/s41467-020-19702-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672105PMC
November 2020

Reply.

Arthritis Rheumatol 2020 Nov 8. Epub 2020 Nov 8.

Corbus Pharmaceuticals, Norwood, MA.

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http://dx.doi.org/10.1002/art.41579DOI Listing
November 2020

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

Clin Rheumatol 2021 Mar 23;40(3):965-971. Epub 2020 Oct 23.

Scleroderma Research Foundation, San Francisco, CA, USA.

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' 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.
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http://dx.doi.org/10.1007/s10067-020-05467-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897231PMC
March 2021

A Mortality Risk Score Model for Clinically Amyopathic Dermatomyositis-Associated Interstitial Lung Disease: Will It Have the Necessary "FLAIR" to Improve Clinical Outcomes?

Chest 2020 Oct;158(4):1307-1309

Department of Dermatology, Stanford University, Stanford, CA.

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http://dx.doi.org/10.1016/j.chest.2020.06.001DOI Listing
October 2020

Gastric antral vascular ectasia in systemic sclerosis: Association with anti-RNA polymerase III and negative anti-nuclear antibodies.

Semin Arthritis Rheum 2020 10 6;50(5):938-942. Epub 2020 Jul 6.

Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, USA; Department of Medicine, Division of Immunology and Rheumatology, Palo Alto Veterans Affairs Healthcare System, USA. Electronic address:

Objective: Gastric antral vascular ectasia (GAVE) is a vascular manifestation of systemic sclerosis (SSc) that can lead to iron deficiency anemia or acute gastrointestinal (GI) bleeding. We aimed to identify clinical features associated with GAVE.

Methods: We performed a cohort study of SSc patients who were seen at Stanford between 2004 and 2018 and had undergone esophagogastroduodenoscopy (EGD). We compared the clinical features of those with and without GAVE, and multivariable logistic regression was performed to identify clinical correlates with GAVE.

Results: A total of 225 patients with SSc who underwent EGD were included in this study and 19 (8.4%) had GAVE. Those with GAVE were more likely to have scleroderma renal crisis (SRC) (21% vs 3%; p < 0.01), positive anti-RNA polymerase III antibody (71% vs 19%; p < 0.01), nucleolar pattern of anti-nuclear antibody (ANA) (33% vs 11%; p=0.04), and negative ANA (<1:80 by immunofluorescence) (33% vs 11%; p=0.02). On multivariate analysis with multiple imputation, anti-RNA polymerase III positivity (OR 4.57; 95% CI (1.57 - 13.23), p < 0.01) and ANA negativity (OR 3.75; 95% CI (1.21 - 11.62), p=0.02) remained significantly associated with GAVE.

Conclusion: Positive anti-RNA polymerase III antibody and ANA negativity were significantly associated with GAVE. Further studies are necessary to determine whether patients with these autoantibody profiles should undergo screening endoscopies for GAVE.
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http://dx.doi.org/10.1016/j.semarthrit.2020.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584748PMC
October 2020

Calcinosis is associated with ischemic manifestations and increased disability in patients with systemic sclerosis.

Semin Arthritis Rheum 2020 10 17;50(5):891-896. Epub 2020 Jun 17.

Stanford University School of Medicine and Palo Alto VA Health Care System, Department of Immunology and Rheumatology and Dermatology (by courtesy), USA. Electronic address:

Objective: Calcinosis is a debilitating complication of systemic sclerosis (SSc) with no effective treatments. We sought to identify clinical correlations and to characterize complications and disability associated with calcinosis in a multi-center, international cohort of SSc patients.

Methods: We established a cohort of 568 consecutive SSc patients who fulfill 2013 revised ACR/EULAR criteria at 10 centers within North America, Australia, and Mexico. Calcinosis was defined as subcutaneous calcium deposition by imaging and/or physical examination, or a clear history of extruded calcium. All patients completed the Scleroderma Health Assessment Questionnaire Disability Index and Cochin Hand Functional Scale.

Results: 215 (38%) patients had calcinosis. In multivariable analysis, disease duration (OR=1.24, p = 0.029), digital ischemia (OR=1.8, p = 0.002) and Acro-osteolysis (OR=2.97, p = 0.008) were significantly associated with calcinosis. In the subset of patients with bone densitometry (n = 68), patients with calcinosis had significantly lower median T-scores than patients without (-2.2 vs. -1.7, p = 0.004). The most common location of calcinosis lesions was the hands (70%), particularly the thumbs (19%) with decreasing frequency moving to the fifth fingers (8%). The most common complications were tenderness (29% of patients) and spontaneous extrusion of calcinosis through the skin (20%), while infection was rare (2%). Disability and hand function were worse in patients with calcinosis, particularly if locations in addition to the fingers/thumbs were involved.

Conclusions: We confirmed a strong association between calcinosis and digital ischemia. Calcinosis in SSc patients most commonly affects the hands and is associated with a high burden of disability and hand dysfunction.
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http://dx.doi.org/10.1016/j.semarthrit.2020.06.007DOI Listing
October 2020

CD47 prevents the elimination of diseased fibroblasts in scleroderma.

JCI Insight 2020 08 20;5(16). Epub 2020 Aug 20.

Department of Pathology.

Scleroderma is a devastating fibrotic autoimmune disease. Current treatments are partly effective in preventing disease progression but do not remove fibrotic tissue. Here, we evaluated whether scleroderma fibroblasts take advantage of the "don't-eat-me-signal" CD47 and whether blocking CD47 enables the body's immune system to get rid of diseased fibroblasts. To test this approach, we used a Jun-inducible scleroderma model. We first demonstrated in patient samples that scleroderma upregulated transcription factor JUN and increased promoter accessibilities of both JUN and CD47. Next, we established our scleroderma model, demonstrating that Jun mediated skin fibrosis through the hedgehog-dependent expansion of CD26+Sca1- fibroblasts in mice. In a niche-independent adaptive transfer model, JUN steered graft survival and conferred increased self-renewal to fibroblasts. In vivo, JUN enhanced the expression of CD47, and inhibiting CD47 eliminated an ectopic fibroblast graft and increased in vitro phagocytosis. In the syngeneic mouse, depleting macrophages ameliorated skin fibrosis. Therapeutically, combined CD47 and IL-6 blockade reversed skin fibrosis in mice and led to the rapid elimination of ectopically transplanted scleroderma cells. Altogether, our study demonstrates the efficiency of combining different immunotherapies in treating scleroderma and provides a rationale for combining CD47 and IL-6 inhibition in clinical trials.
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http://dx.doi.org/10.1172/jci.insight.140458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455137PMC
August 2020

Ultrasound Detection of Calcinosis and Association with Ulnar Artery Occlusion in Patients with Systemic Sclerosis.

Arthritis Care Res (Hoboken) 2020 May 31. Epub 2020 May 31.

Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA, USA.

Objective: To investigate the ability of ultrasound (US) compared to radiographs in detecting calcinosis in hands/wrists of systemic sclerosis (SSc) patients, and assess US markers of pathologic perfusion.

Methods: SSc patients were evaluated for calcinosis in the hands/wrists by X-ray and US. Presence or absence of calcinosis was recorded by patient, hand, and anatomical zone; sensitivity and specificity for calcinosis detection by US versus X-ray was determined. Bilateral US vascular measurements of ulnar artery occlusion (UAO) and finger pulp blood flow (FPBF) were obtained. For each hand, associations between markers of pathologic blood flow (UAO, FPBF, and a composite severity score of UAO and FPBF) and presence of calcinosis were assessed using generalized estimating equations.

Results: Of 43 SSc patients (19 diffuse, 24 limited), 39.5% had calcinosis on X-ray compared to 30.2% on US. Sensitivity and specificity for US was 61% and 95% by zone, 78% and 98% by hand, and 76% and 100% by patient, respectively. UAO was seen in 30% and 28% of left and right hands, respectively; FPBF was absent in ≥1 digit of the left and right hands in 49% and 44%, respectively. UAO was associated with X-ray identified calcinosis by hand (OR 8.08, 95% CI 2.45-26.60, p<0.001), whereas FPBF and the composite severity score were not significant. UAO was associated with calcinosis even in the absence of digital ulcers (OR 33.00, 95% CI 3.39-321.09, p=0.003).

Conclusion: US was sensitive and highly specific in detecting calcinosis in SSc. UAO was strongly associated with X-ray identified calcinosis.
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http://dx.doi.org/10.1002/acr.24327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704806PMC
May 2020

Development and Assessment of a Novel Lung Ultrasound Interpretation Criteria for the Detection of Interstitial Lung Disease in Systemic Sclerosis.

Arthritis Care Res (Hoboken) 2020 May 31. Epub 2020 May 31.

Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA, USA.

Objectives: Interstitial lung disease (ILD) is a frequent complication of systemic sclerosis (SSc), and ILD screening, characterization, and monitoring are important for therapeutic decision-making and prognostication. Lung ultrasonography (LUS) is a potential alternative imaging modality for ILD detection. In this study, we develop and test a novel LUS examination technique and interpretation criteria for detecting SSc-ILD.

Methods: LUS acquisition was performed by collecting short ultrasound movies at 14 lung positions. LUS interpretation criteria for SSc-ILD detection focused on visualized pleural changes. To assess the performance of our methodology for SSc-ILD detection, we prospectively enrolled SSc patients with high resolution computed tomography (HRCT) imaging within 3 months of LUS. LUS exams were scored independently by two blinded readers (one ultrasonographer and one non-ultrasonographer). The sensitivity and specificity for SSc-ILD detection was assessed and agreement was measured with Cohen's Kappa statistic.

Results: To test the performance of our LUS acquisition technique and interpretation criteria, 20 SSc patients were evaluated by LUS (278 lung zones) and HRCT. HRCT confirmed ILD in 9 patients (45%). LUS was positive for SSc-ILD in 11 patients (55%) with a sensitivity of 100% and specificity of 82% versus HRCT, with perfect agreement between the two readers (κ=1). Analysis by individual lung zones found excellent agreement between readers with 93.8% concordance and κ=0.82.

Conclusion: We developed a novel LUS examination technique and interpretation criteria that are highly sensitive and specific for SSc-ILD detection in an SSc cohort, affording perfect agreement between ultrasonographer and non-ultrasonographer readers.
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http://dx.doi.org/10.1002/acr.24338DOI Listing
May 2020

A Novel Utility to Correct for Plate/Batch/Lot and Nonspecific Binding Artifacts in Luminex Data.

J Immunol 2020 06 6;204(12):3425-3433. Epub 2020 May 6.

Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.

Cytokines and other secreted soluble proteins are routinely assayed as fluorescence intensities on the Luminex (Luminex, Austin, TX) platform. As with any immunoassay, a portion of the measured Ab binding can be nonspecific. Use of spiked-in microbead controls (e.g., AssayChex Process, Control Panel; Radix Biosolutions, Georgetown, TX) can determine the level of nonspecific binding on a per specimen basis. A statistical approach for correction of this assay's nonspecific binding artifact was first described in earlier work. The current paper describes a novel utility written in the R language (https://www.r-project.org), that refines correction for nonspecific binding in three important ways: 1) via local polynomial regression, the utility allows for curvature in relationships between soluble protein median fluorescence intensities and nonspecific binding median fluorescence intensities; 2) to stabilize correction, the fit of the nonlinear regression function is obtained via repeated cross-validation; and 3) the utility addresses possible bias due to technical error in measured nonspecific binding. The utility first logarithm transforms and then removes plate/batch/lot artifacts from median fluorescence intensities prior to correction for nonspecific binding, even when plates/batches/lots are unbalanced with respect to experimental factors of interest. Continuous (e.g., age) and categorical (e.g., diagnosis) covariates are accommodated in plate/batch/lot artifact correction. We present application of the utility to a panel of 62 cytokines in a sample of human patients diagnosed with systemic sclerosis and to an experiment that examined multiple lots of a human 51-cytokine panel. The R script for our new utility is publicly available for download from the web.
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http://dx.doi.org/10.4049/jimmunol.2000017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891557PMC
June 2020

Safety and Efficacy of Lenabasum in a Phase II, Randomized, Placebo-Controlled Trial in Adults With Systemic Sclerosis.

Arthritis Rheumatol 2020 08 17;72(8):1350-1360. Epub 2020 Jul 17.

Corbus Pharmaceuticals, Norwood, Massachusetts.

Objective: To assess the safety and efficacy of lenabasum in diffuse cutaneous systemic sclerosis (dcSSc).

Methods: A randomized, double-blind, placebo-controlled, phase II study was conducted at 9 SSc clinics in the US. Adults with dcSSc of ≤6 years' duration who were receiving stable standard-of-care treatment were randomized to receive lenabasum (n = 27) or placebo (n = 15). Lenabasum doses were 5 mg once daily, 20 mg once daily, or 20 mg twice daily for 4 weeks, followed by 20 mg twice daily for 8 weeks. Safety and efficacy were assessed at weeks 4, 8, 12, and 16.

Results: Adverse events (AEs) occurred in 63% of the lenabasum group and 60% of the placebo group, with no serious AEs related to lenabasum. Compared to placebo, lenabasum treatment was associated with greater improvement in the American College of Rheumatology Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) score and other efficacy outcome measures that assessed overall disease, skin involvement, and patient-reported function. The median CRISS score increased in the lenabasum group during the study, reaching 0.33, versus 0.00 in the placebo group, at week 16 (P = 0.07 by 2-sided mixed-effects model repeated-measures analysis). Gene expression in inflammation and fibrosis pathways was reduced, and inflammation and fibrosis were improved on histologic evaluation of skin biopsy specimens, in the lenabasum group compared to the placebo group (all P ≤ 0.05).

Conclusion: Despite a short trial duration in a small number of patients in this phase II study in dcSSc, our findings indicate that lenabasum improves efficacy outcomes and underlying disease pathology with a favorable safety profile.
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http://dx.doi.org/10.1002/art.41294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497006PMC
August 2020

The Scleroderma Patient-Centered Intervention Network Self-Management Program: Protocol for a Randomized Feasibility Trial.

JMIR Res Protoc 2020 04 24;9(4):e16799. Epub 2020 Apr 24.

See Acknowledgments, .

Background: Systemic sclerosis (SSc), or scleroderma, is a rare disease that often results in significant disruptions to activities of daily living and can negatively affect physical and psychological well-being. Because there is no known cure, SSc treatment focuses on reducing symptoms and disability and improving health-related quality of life (HRQoL). Self-management programs are known to increase self-efficacy for disease management in many chronic diseases. The Scleroderma Patient-centered Intervention Network (SPIN) developed a Web-based self-management program (SPIN self-management; SPIN-SELF) to increase self-efficacy for disease management and to improve HRQoL for patients with SSc.

Objective: The proposed study aims to assess the feasibility of conducting a full-scale randomized controlled trial (RCT) of the SPIN-SELF program by evaluating the trial implementation processes, required resources and management, scientific aspects, and participant acceptability and usage of the SPIN-SELF program.

Methods: The SPIN-SELF feasibility trial will be conducted via the SPIN Cohort. The SPIN Cohort was developed as a framework for embedded pragmatic trials using the cohort multiple RCT design. In total, 40 English-speaking SPIN Cohort participants with low disease management self-efficacy (Self-Efficacy for Managing Chronic Disease Scale score ≤7), who have indicated interest in using a Web-based self-management program, will be randomized with a 3:2 ratio into the SPIN-SELF program or usual care for 3 months. Feasibility outcomes include trial implementation processes, required resources and management, scientific aspects, and patient acceptability and usage of the SPIN-SELF program.

Results: Enrollment of the 40 participants occurred between July 5, 2019, and July 27, 2019. By November 25, 2019, data collection of trial outcomes was completed. Data analysis is underway, and results are expected to be published in 2020.

Conclusions: The SPIN-SELF program is a self-help tool that may improve disease-management self-efficacy and improve HRQoL in patients with SSc. The SPIN-SELF feasibility trial will ensure that trial methodology is robust, feasible, and consistent with trial participant expectations. The results will guide adjustments that need to be implemented before undertaking a full-scale RCT of the SPIN-SELF program.

International Registered Report Identifier (irrid): DERR1-10.2196/16799.
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http://dx.doi.org/10.2196/16799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210498PMC
April 2020

Calcinosis Biomarkers in Adult and Juvenile Dermatomyositis.

Autoimmun Rev 2020 Jun 28;19(6):102533. Epub 2020 Mar 28.

Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA; VA Palo Alto Health Care System, Palo Alto, CA, USA. Electronic address:

Dermatomyositis (DM) is a rare idiopathic inflammatory myopathy characterized by muscle weakness and cutaneous manifestations in adults and children. Calcinosis, a complication of DM, is the abnormal deposition of insoluble calcium salts in tissues, including skin, subcutaneous tissue, tendons, fascia, and muscle. Calcinosis is more commonly seen in juvenile DM (JDM), but also develops in adult DM. Although the mechanism of calcinosis remains unclear, several pathogenic hypotheses have been proposed, including intracellular accumulation of calcium secondary to an alteration of the cellular membrane by trauma and inflammation, local vascular ischemia, dysregulation of mechanisms controlling the deposition and solubility of calcium and phosphate, and mitochondrial damage of muscle cells. Identifying calcinosis biomarkers is important for early disease detection and risk assessment, and may lead to novel therapeutic targets for the prevention and treatment of DM-associated calcinosis. In this review, we summarize myositis autoantibodies associated with calcinosis in DM, histopathology and chemical composition of calcinosis, genetic and inflammatory markers that have been studied in adult DM and JDM-associated calcinosis, as well as potential novel biomarkers.
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http://dx.doi.org/10.1016/j.autrev.2020.102533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225028PMC
June 2020

Increased Mortality in Asians With Systemic Sclerosis in Northern California.

ACR Open Rheumatol 2020 Apr 21;2(4):197-206. Epub 2020 Mar 21.

Stanford University School of Medicine and Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, California.

Objective: The objective of this study is to evaluate racial/ethnic differences in disease manifestations and survival in a US cohort of patients with systemic sclerosis (SSc), with a focus on Asian patients.

Methods: A retrospective cohort study was conducted among Kaiser Permanente Northern California adults with an incident SSc diagnosis by a rheumatologist from 2007 to 2016, confirmed by a chart review to fulfill 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria. Self-reported race/ethnicity was categorized as non-Hispanic white, Asian, Hispanic, and black. Disease manifestations and survival were compared, using white patients as the reference.

Results: A total of 609 patients with incident SSc were identified: 89% were women, and 81% had limited cutaneous SSc, with a mean age at diagnosis of 55.4 ± 14.8 years. The racial/ethnic distribution was 51% non-Hispanic white (n = 310), 25% Hispanic (n = 154), 16% Asian (n = 96), and 8% black (n = 49). Compared with white patients, black patients had a greater prevalence of diffuse disease (14.5% vs. 44.9%; P < 0.001), and Asians had higher rates of anti-U1-RNP antibodies (32.1% vs. 11.9%; P = 0.005). Nine-year overall survival rates following SSc diagnosis were lower in Asian (52.3%), black (52.2%), and Hispanic patients (68.2%) compared with white patients (75.8%). Pulmonary hypertension and infections were the leading causes of death in Asian patients. Asian race was associated with higher mortality on univariable (hazard ratio [HR] 1.83 [95% confidence interval (CI) 1.08-2.99]; P = 0.020) and multivariable analyses (HR 1.80 [95% CI 0.99-3.16]; P = 0.047) when adjusting for age, sex, body mass index, cutaneous subtype, smoking status, interstitial lung disease, pulmonary hypertension, renal crisis, and malabsorption syndrome.

Conclusion: Asian patients with SSc in this US cohort had increased mortality compared with white patients. These patients warrant close monitoring for disease progression.
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http://dx.doi.org/10.1002/acr2.11126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164633PMC
April 2020

Drugs in phase I and phase II clinical trials for systemic sclerosis.

Expert Opin Investig Drugs 2020 Apr 25;29(4):349-362. Epub 2020 Mar 25.

Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA, USA.

: Systemic sclerosis (SSc) is an autoimmune connective tissue disease that is characterized by excessive collagen deposition, vascular dysfunction, and fibrosis of cutaneous and visceral organs. Current therapeutic options are limited and provide only modest benefit.: This review summarizes investigational agents in recent Phase I and II clinical trials evaluated for the treatment of SSc with a focus on skin in patients with early diffuse disease and interstitial lung disease. We performed a search on Pubmed and https://clinicaltrials.gov with keywords systemic sclerosis, Phase I clinical trial, and Phase II clinical trial to identify relevant studies from 2015 to 2019.: Therapeutic interventions in SSc should be guided by the level of disease activity and the degree of organ involvement. While most novel agents have failed to meet the primary endpoints of reducing skin thickening as measured by the modified Rodnan skin score, some have shown promise in improving the Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis (CRISS), reducing lung function decline, or improving patient-reported outcomes. However, most of the current evidence is based on small or open-label clinical trials. Well-designed, large, randomized, Phase III clinical trials are necessary to define the roles of investigational agents in treating SSc.
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http://dx.doi.org/10.1080/13543784.2020.1743973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174094PMC
April 2020

Raynaud phenomenon and digital ulcers in systemic sclerosis.

Nat Rev Rheumatol 2020 04 25;16(4):208-221. Epub 2020 Feb 25.

Division of Rheumatology, University of Florence, Florence, Italy.

Raynaud phenomenon is a symptom complex caused by impaired digital perfusion and can occur as a primary phenomenon or secondary to a wide range of underlying causes. Raynaud phenomenon occurs in virtually all patients with systemic sclerosis (SSc) and is often the earliest clinical manifestation to occur. Careful assessment is required in patients with Raynaud phenomenon to avoid missing secondary causes such as SSc. Digital ulcers are a painful and disabling visible manifestation of digital vascular injury in patients with SSc. Progress has been made in the classification and assessment of digital ulcers and in understanding ulcer pathogenesis, and there are a wide range of treatments available to both prevent and heal digital ulcers, some of which are also used in Raynaud phenomenon management. In this Review, the assessment of patients with Raynaud phenomenon is discussed, including 'red flags' that are suggestive of SSc. The pathogenesis, classification and assessment of SSc-associated digital ulcers are also covered, alongside an overview of management approaches for SSc-associated Raynaud phenomenon and digital ulcers. Finally, unmet needs are discussed and the concept of a unified vascular phenotype in which therapies that affect the vasculature to support disease modification strategies is introduced.
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http://dx.doi.org/10.1038/s41584-020-0386-4DOI Listing
April 2020

and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry.

Proc Natl Acad Sci U S A 2020 01 23;117(1):552-562. Epub 2019 Dec 23.

Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.

Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant * and * alleles were associated with overall SSc risk, and the * allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the * and * alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of in defining autoantibody subtypes. The association of the * allele with the ATA subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and * allele frequency in multiple populations was observed ( = 0.98, = 3 × 10). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/β allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.
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http://dx.doi.org/10.1073/pnas.1906593116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955366PMC
January 2020

Collaborative National Quality and Efficacy Registry (CONQUER) for Scleroderma: outcomes from a multicenter US-based systemic sclerosis registry.

Clin Rheumatol 2020 Jan 30;39(1):93-102. Epub 2019 Oct 30.

Division of Rheumatology, McGovern Medical School at the University of Texas Health Science Center at Houston, Houston, TX, USA.

The Collaborative National Quality and Efficacy Registry (CONQUER) for Scleroderma is a multicenter US-based longitudinal study of patients with systemic sclerosis (SSc) within 5 years of first non-Raynaud's symptom. The data collection methodology incorporates successful models from other SSc registries. The cohort is designed to provide linked bio-specimen and clinical outcomes data on a longitudinal cohort of SSc patients for validation of hypothesis-driven research and to provide a platform for studying patient-reported outcomes in scleroderma. The CONQUER registry was developed using the guidelines of the International Society for Biological Repositories, and was an iterative process between physicians with an expertise in SSc, patient stakeholders, and information technology experts. Enrollment commenced in June 2018. During the first 6 months of the CONQUER Scleroderma study, 151 SSc patients with less than 5 years of disease duration (from first non-Raynaud's symptom) have been recruited. The mean age is 51 ± 14 years, 83% are female, and 60% of patients have diffuse disease. Survey completion rates are above 88% for all patient-reported outcome surveys. Bio-specimen collection rates are over 97%, and disease severity score completion rates are over 98%. Pulmonary function test data is available on 91% of patients, and echocardiography is available 80%. The CONQUER scleroderma study provides a unique and growing resource for studying scleroderma in a longitudinal, US-based population. KEY POINTS : • The Collaborative National Quality and Efficacy Registry (CONQUER) for Scleroderma is a multicenter US-based longitudinal study of patients with systemic sclerosis (SSc) within 5 years of first non-Raynaud's symptom. • The CONQUER scleroderma study provides a unique and growing resource for studying scleroderma in a longitudinal, US-based population. • CONQUER is innovative in its design in that it is focused on prospective collection of paired clinical and patient outcome data with bio-specimens.
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http://dx.doi.org/10.1007/s10067-019-04792-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280746PMC
January 2020

Abatacept in Early Diffuse Cutaneous Systemic Sclerosis: Results of a Phase II Investigator-Initiated, Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial.

Arthritis Rheumatol 2020 01 10;72(1):125-136. Epub 2019 Dec 10.

University of California, Los Angeles.

Objective: T cells play a key role in the pathogenesis of early systemic sclerosis. This study was undertaken to assess the safety and efficacy of abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc).

Methods: In this 12-month, randomized, double-blind, placebo-controlled trial, participants were randomized 1:1 to receive either subcutaneous abatacept 125 mg or matching placebo, stratified by duration of dcSSc. Escape therapy was allowed at 6 months for worsening disease. The coprimary end points were change in the modified Rodnan skin thickness score (MRSS) compared to baseline and safety over 12 months. Differences in longitudinal outcomes were assessed according to treatment using linear mixed models, with outcomes censored after initiation of escape therapy. Skin tissue obtained from participants at baseline was classified into intrinsic gene expression subsets.

Results: Among 88 participants, the adjusted mean change in the MRSS at 12 months was -6.24 units for those receiving abatacept and -4.49 units for those receiving placebo, with an adjusted mean treatment difference of -1.75 units (P = 0.28). Outcomes for 2 secondary measures (Health Assessment Questionnaire disability index and a composite measure) were clinically and statistically significantly better with abatacept. The proportion of subjects in whom escape therapy was needed was higher in the placebo group relative to the abatacept group (36% versus 16%). In the inflammatory and normal-like skin gene expression subsets, decline in the MRSS over 12 months was clinically and significantly greater in the abatacept group versus the placebo group (P < 0.001 and P = 0.03, respectively). In the abatacept group, adverse events occurred in 35 participants versus 40 participants in the placebo group, including 2 deaths and 1 death, respectively.

Conclusion: In this phase II trial, abatacept was well-tolerated, but change in the MRSS was not statistically significant. Secondary outcome measures, including gene expression subsets, showed evidence in support of abatacept. These data should be confirmed in a phase III trial.
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http://dx.doi.org/10.1002/art.41055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935399PMC
January 2020

An Interim Report of the Scleroderma Clinical Trials Consortium Working Groups.

J Scleroderma Relat Disord 2019 Feb 18;4(1):17-27. Epub 2018 Jul 18.

Rheumatology Unit, University Hospital of Cagliari.

The Scleroderma Clinical Trials Consortium (SCTC) represents many of the clinical researchers in the world who are interested in improving the efficiency of clinical trials in Systemic Sclerosis (SSc). The SCTC has established 11 working groups (WGs) to develop and validate better ways of measuring and recording multiple aspects of this heterogeneous disease. These include groups working on arthritis, disease damage, disease activity, cardiac disease, juvenile SSc, the gastrointestinal tract, vascular component, calcinosis, scleroderma renal crisis, interstitial lung disease, and skin measurement. Members of the SCTC may join any one or more of these groups. Some of the WGs have only recently started their work, some are nearing completion of their mandated tasks and others are in the midst of their projects. All these projects, which are described in this paper, will help to improve clinical trials and observational studies by improving or developing better, more sensitive ways of measuring various aspects of the disease. As Lord Kelvin stated, "To measure is to know. If you cannot measure it you cannot improve it." The SCTC is dedicated to improving the lives of patients with SSc and it is our hope that the contributions of the WGs will be one important step in this process.
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http://dx.doi.org/10.1177/2397198318783926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428445PMC
February 2019

Upper Extremity Angiographic Patterns in Systemic Sclerosis: Implications for Surgical Treatment.

J Hand Surg Am 2019 Nov 21;44(11):990.e1-990.e7. Epub 2019 Feb 21.

Division of Plastic Surgery, Stanford University School of Medicine, Palo Alto, CA. Electronic address:

Purpose: Conventional angiography is often used in the preoperative work-up of hand surgery patients with systemic sclerosis. The goal of this study was to propose a classification system based on the pattern of arterial involvement in a series of upper extremity angiograms. The authors hypothesized that this classification system would demonstrate high inter- and intrarater reliability.

Methods: A retrospective review of 110 upper extremity angiograms in patients with systemic sclerosis (obtained between 1996 and 2017) was performed. Images were classified into 4 types based on the patency of the radial and ulnar arteries at the wrist, and into 3 subtypes based on the patency of the superficial and deep palmar arches. Classification reliability was compared with Fleiss' Kappa (for inter-rater) and Cohen's (for intrarater) coefficient between 4 fellowship-trained hand surgeons and a hand fellow.

Results: The inter-rater reliability between all 5 observers using types alone was 0.83 (0.80-0.85), whereas the inter-rater reliability using subtypes was 0.64 (confidence interval [CI] 95%, 0.62-0.65). The intrarater reliability using types alone ranged from 0.80 to 0.95, whereas intrarater reliabilities using subtypes were 0.81 (CI 95%, 0.72-0.90), 0.78 (CI 95%, 0.69-0.87), 0.87 (CI 95%, 0.80-0.95), 0.64 (CI 95%, 0.53-0.75), and 0.92 (CI 95%, 0.86-0.98) for the 4 attendings and a hand fellow, respectively. Fifty-seven percent of angiograms were interpreted as having loss of ulnar artery patency at the wrist (type 2) with 77% having additional loss of superficial palmar arch patency (type 2A).

Conclusions: This large series of angiograms in patients with systemic sclerosis demonstrates a classification system for conventional angiography that shows high inter-rater and intrarater reliability using type alone. When subtypes were used, the inter-rater and intrarater reliabilities decreased to moderate and moderate-to-high, respectively.

Clinical Relevance: This study represents the first step in establishing a classification system that, by grouping patients with similar angiogram findings, may allow for targeted research into risk stratification, monitoring, and treatment in systemic sclerosis.
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http://dx.doi.org/10.1016/j.jhsa.2019.01.004DOI Listing
November 2019

Risk Factors for Mortality and Cardiopulmonary Hospitalization in Systemic Sclerosis Patients At Risk for Pulmonary Hypertension, in the PHAROS Registry.

J Rheumatol 2019 02 1;46(2):176-183. Epub 2018 Oct 1.

From the Department of Medicine, Division of Rheumatology, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey; Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, California; Department of Medicine, Division of Rheumatology, Johns Hopkins University, Baltimore, Maryland; Department of Medicine, Division of Rheumatology, Boston University, Boston; Department of Medicine, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, South Carolina; Department of Medicine, Division of Rheumatology, and Pulmonary Sciences and Critical Care Medicine, University of Colorado, Denver, Colorado; Department of Medicine, Division of Rheumatology, Northwestern University, Chicago, Illinois; Department of Medicine, Division of Rheumatology, New York University Medical Center, New York, New York; Department of Medicine, Division of Rheumatology, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan; Department of Medicine, Division of Rheumatology, Albany Medical College, Albany, New York; Department of Medicine, Division of Rheumatology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Medicine, Division of Rheumatology, University of Texas, Houston, Texas; Department of Medicine, Division of Rheumatology, University of California at Los Angeles, Los Angeles, California; Department of Medicine, Division of Rheumatology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Medicine, Division of Rheumatology, University of Minnesota, Minneapolis, Minnesota; Department of Medicine, Divisions of Pulmonary and Rheumatology, Tulane University, New Orleans, Louisiana; Department of Epidemiology and Health Promotion, New York University, New York, New York; Department of Medicine, Division of Rheumatology, Immunology and Allergy, Georgetown University, Washington, D.C., USA.

Objective: We sought to identify predictors of mortality and cardiopulmonary hospitalizations in patients at risk for pulmonary hypertension (PH) and enrolled in PHAROS, a prospective cohort study to investigate the natural history of PH in systemic sclerosis (SSc).

Methods: The at-risk population for PH was defined by the following entry criteria: echocardiogram systolic pulmonary arterial pressure > 40 mmHg, or DLCO < 55% predicted or ratio of % forced vital capacity/%DLCO > 1.6, measured by pulmonary function testing. Baseline clinical measures were evaluated as predictors of hospitalization and death between 2005 and 2014. Cox proportional hazards models were censored at date of PH onset or latest study visit and adjusted for age, sex, race, and disease duration.

Results: Of the 236 at-risk subjects who were followed for a median of 4 years (range 0.4-8.5 yrs), 35 developed PH after entering PHAROS (reclassified as PH group). In the at-risk group, higher mortality was strongly associated with male sex, low %DLCO, exercise oxygen desaturation, anemia, abnormal dyspnea scores, and baseline pericardial effusion. Risks for cardiopulmonary hospitalization were associated with increased dyspnea and pericardial effusions, although PH patients with DLCO < 50% had the highest risk of cardiopulmonary hospitalizations.

Conclusion: Risk factors for poor outcome in patients with SSc who are at risk for PH were similar to others with SSc-PH and SSc-pulmonary arterial hypertension, including male sex, DLCO < 50%, exercise oxygen desaturation, and pericardial effusions. This group should undergo right heart catheterization and receive appropriate intervention if PH is confirmed.
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http://dx.doi.org/10.3899/jrheum.180018DOI Listing
February 2019

Calcinosis in scleroderma.

Curr Opin Rheumatol 2018 11;30(6):554-561

Stanford University School of Medicine and Palo Alto VA Healthcare System, Division of Immunology and Rheumatology, and Dermatology, Palo Alto, California, USA.

Purpose Of Review: To provide an update on the available literature regarding the epidemiology, pathophysiology, diagnosis, and treatment of calcinosis cutis in patients with systemic sclerosis (SSc).

Recent Findings: We identified observational studies that describe the frequency of calcinosis in SSc and associated clinical features; molecular studies exploring potential pathogenic mechanisms; and case reports and case series describing new diagnostic approaches and treatments.

Summary: Calcinosis cutis is the deposition of insoluble calcium in the skin and subcutaneous tissues. It represents a major clinical problem in patients with SSc affecting at least one quarter of patients. It is associated with longer disease duration, digital ulcers, acro-osteolysis, positive anticentromere antibody, and positive anti-PM/Scl antibody. Although pathogenesis is unknown, there is evidence supporting local trauma, chronic inflammation, vascular hypoxia, and dysregulation of bone matrix proteins as potential mechanisms. Diagnosis can be made clinically or with plain radiography. Several pharmacologic therapies have been tried for calcinosis with variable and modest results, but surgical excision of calcium deposits remains the mainstay of treatment.
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http://dx.doi.org/10.1097/BOR.0000000000000539DOI Listing
November 2018