[Show abstract][Hide abstract] ABSTRACT: Systemic sclerosis (SSc)-related interstitial lung disease (ILD) has phenotypic similarities to lung involvement in idiopathic interstitial pneumonia (IIP). We aimed to assess whether genetic susceptibility loci recently identified in the large IIP genome-wide association studies (GWASs) were also risk loci for SSc overall or severity of ILD in SSc.
A total of 2571 SSc patients and 4500 healthy controls were investigated from the US discovery GWAS and additional US replication cohorts. Thirteen IIP-related selected single nucleotide polymorphisms (SNPs) were genotyped and analyzed for their association with SSc.
We found an association of SSc with the SNP rs6793295 in the LRRC34 gene (OR = 1.14, CI 95 % 1.03 to 1.25, p value = 0.009) and rs11191865 in the OBFC1 gene (OR = 1.09, CI 95 % 1.00 to 1.19, p value = 0.043) in the discovery cohort. Additionally, rs7934606 in MUC2 (OR = 1.24, CI 95 % 1.01 to 1.52, p value = 0.037) was associated with SSc-ILD defined by imaging. However, these associations failed to replicate in the validation cohort. Furthermore, SNPs rs2076295 in DSP (β = -2.29, CI 95 % -3.85 to -0.74, p value = 0.004) rs17690703 in SPPL2C (β = 2.04, CI 95 % 0.21 to 3.88, p value = 0.029) and rs1981997 in MAPT (β = 2.26, CI 95 % 0.35 to 4.17, p value = 0.02) were associated with percent predicted forced vital capacity (FVC%) even after adjusting for the anti-topoisomerase (ATA)-positive subset. However, these associations also did not replicate in the validation cohort.
Our results add new evidence that SSc and SSc-related ILD are genetically distinct from IIP, although they share phenotypic similarities.
Preview · Article · Dec 2016 · Arthritis research & therapy
[Show abstract][Hide abstract] ABSTRACT: The gastrointestinal tract (GIT) is the most common extracutaneous organ system damaged in systemic sclerosis (SSc) and is the presenting feature in 10% of patients. The esophagus as the portion of the GIT is the most commonly affected and there is an association of gastroesophageal reflux (GER) with SSc interstitial lung disease (ILD). Thus, an aggressive treatment for GER is recommended in all SSc patients with ILD; however, it is recognized that a long-term benefit to this treatment is needed to understand its impact. In this case report we discuss the presence of eosinophilic esophagitis (EoE) in two SSc patients and discuss the role for early EGD in SSc patients with moderate-severe GER symptoms for tissue study. Assessment of esophageal biopsy specimens for the presence of eosinophils and possibly ANA can help elucidate disease pathogenesis and direct therapy, as the presence of EoE in SSc has important management considerations, particularly with regards to dietary modification strategies.
[Show abstract][Hide abstract] ABSTRACT: Background: Sublingual frenulum abnormalities have been observed in systemic sclerosis (SSc), but the clinical significance of such features is not known. The goal of this project was to devise a reliable bedside tool to confirm the presence of sublingual frenulum abnormalities in SSc and explore potential associations with patient demographics and gastrointestinal clinical phenotype. Methods: A working group was created to develop a semiquantitative assessment tool for assessing sublingual abnormalities, the Sublingual Abnormalities Index (SAI). Sublingual frenulum thickness, frenulum length, sublingual buccal mucosa pallor, and the presence of oral telangiectasia were each individually scored using 0- to 2-point Likert scales and a composite score of the 4 domains created by summation of the individual scores. Assessment of the sublingual region of 21 patients with SSc and 8 control subjects was undertaken. An image of the sublingual frenulum was obtained using prespecified camera settings to allow assessment of interrater reliability with 2 independent blinded assessors. Results: Scores for each of the SAI domains differed between control subject and SSc population (P = 0.0003). Patients with SSc had a composite SAI score of 4.3 (SD, 0.37). None of the control subjects had a composite SAI score of more than 2. There was excellent interrater reliability between clinician assessment and each blinded assessor (Cohen κ's of 0.72 and 0.82, respectively). Conclusions: This feasibility study confirms the presence of clinical sublingual abnormalities in SSc, which can be categorized using a simple scoring chart withmoderate to near-perfect interrater agreement. The functional significance and pathogenesis of this abnormality warrant further study.
No preview · Article · Jan 2016 · JCR Journal of Clinical Rheumatology
[Show abstract][Hide abstract] ABSTRACT: Objective:
Self-management programs for patients with chronic illnesses, including rheumatic diseases, seek to enhance self-efficacy for performing health management behaviors. No measure of self-efficacy has been validated for patients with systemic sclerosis (SSc). The objective of this study was to assess the validity and internal consistency reliability of the Self-Efficacy for Managing Chronic Disease (SEMCD) Scale in SSc.
English-speaking SSc patients enrolled in the Scleroderma Patient-centered Intervention Network Cohort who completed the SEMCD Scale at their baseline assessment between March 2014 and June 2015 were included. Patients were enrolled from 21 sites in Canada, the United States and the United Kingdom. Confirmatory factor analysis (CFA) was used to evaluate the factor structure of the SEMCD Scale. Cronbach's alpha was calculated to assess internal consistency reliability. Hypotheses on the direction and magnitude of Pearson's correlations with psychological and physical outcome measures were formulated and tested to examine convergent validity.
A total of 553 patients were included. CFA supported the single-factor structure of the SEMCD Scale (Tucker Lewis Index = 0.99, Comparative Fit Index = 0.99, Root Mean Square Error of Approximation = 0.10). Internal consistency was high (α = 0.93), and correlations with measures of psychological and physical functioning were moderate to large (|r| = 0.48 - 0.67, P < 0.001), confirming study hypotheses.
Scores from the SEMCD Scale are valid for measuring self-efficacy in patients with SSc, and results support using the scale as an outcome measure to evaluate the effectiveness of self-management programs in SSc. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Raynaud's phenomenon is a clinical symptom that can commonly present to a primary care provider or generalist. Proper identification of an underlying connective tissue disease in a patient with Raynaud's could allow for the prevention of possible critical digital ischemia. Capillaroscopy is a tool which can identify abnormalities associated with connective tissue disease. Patients presenting with a complaint of Raynaud's phenomenon were assessed with capillaroscopy. In twenty consecutive Raynaud patients, 8 digits were assessed by a ×200 magnification dermatoscope and an image was obtained. Each image was assessed for the following abnormalities: drop-out (<9 capillaries in 1 mm); microhemorrhage; dilated loops; and neoangiogenesis. These 160 images were then shown to 20 primary care physicians, who assessed these same abnormalities. The interrater reliability, a measure of agreement, of individual primary care providers with the expert provider was assessed using kappa statistics. Three raters had slight agreement (in the range 0 to 0.20), one rater had fair agreement (0.21 to 0.40), 11 raters had moderate agreement (0.41 to 0.60), five raters had substantial agreement (0.61 to 0.80), and no rater had almost perfect agreement (0.81 to 1.00) (14). The total agreement from the 20 primary care providers (n = 3,156) was moderate (Κ = 0.50, 95 % CI 0.49, 0.55). For the four providers with the slight to fair interrater reliabilities, the most common disagreement was providing a positive diagnosis when the expert rater diagnosed the digit negative. Ten of the twenty primary care providers provided at least one additional diagnosis following an abnormal diagnosis (n = 35 digits or 35 % of the 1556 abnormal ratings by the primary care providers). The four providers with the poorest interrater reliabilities were not among the ten providers who participated in making these additional specific diagnoses. These providers achieved the moderate agreement with the expert provider for diagnoses of microhemorrhage (Κ = 0.64, 95 % CI 0.57, 0.70), but fair agreement with the expert provider for diagnoses of dilated (Κ = 0.27, 95 % CI 0.20, 0.34) and neoangiogenesis (Κ = 0.22, 95 %CI 0.13, 0.31). Capillaroscopy is a potentially contributive clinical exam skill that could assist primary care providers and generalists in identifying and qualifying changes associated with the common presentation of Raynaud's disease. However, formal training is needed to ensure accuracy and reproducibility. Furthermore, training and scoring systems should address time constraints of busy primary care practitioners.
[Show abstract][Hide abstract] ABSTRACT: Systemic sclerosis (SSc, scleroderma) is characterised by complex multi-organ pathogenesis, including gastrointestinal tract (GIT) disease that remains poorly characterised. Immunosuppression is commonly used to treat inflammatory manifestations of SSc, including the skin, lungs and joints. There is a paucity of data on the effects of immunosuppression on GIT disease in SSc.
This case report and review of the literature presents two clinical cases in which interleukin-6 (IL-6) antagonism was used for early, diffuse skin disease.
In these two cases, IL-6 anta-gonism was associated with an exacerbation of GIT symptoms.
We postulate that IL-6 is important in the repair of GIT mucosa and further studies are warranted to better understand the effects of immunosuppression on SSc-GIT disease.
No preview · Article · Sep 2015 · Clinical and experimental rheumatology
[Show abstract][Hide abstract] ABSTRACT: The connective tissue diseases (CTD) are frequently associated with Interestitial lung diseases (ILD). The presence of an ILD in a patient with CTD is associated with a higher morbidity and mortality. Management of a patient with connective tissue interstitial lung disease (CTD-ILD) depends on disease severity with a focus on improving quality of life. Therapeutic interventions include medications, which aim to prevent progression to fibrosis and decrease inflammation or alveolitis, supplemental oxygen; and pulmonary rehabilitation. Comorbidities including gastroesophageal reflux disease (GERD) and obstructive sleep apnea should be addressed in all CTD-ILD patients. Appropriate referral to support groups, lung transplantation centers, and palliative care are considerations for all patients with CTDILD. The management of a patient with CTD-ILD is a multidisciplinary personalized process that is driven by the specific disease, clinical pattern, and associated comorbidities.
No preview · Article · Jun 2015 · Current Respiratory Medicine Reviews
[Show abstract][Hide abstract] ABSTRACT: Diffuse systemic sclerosis is associated with high mortality; however, the pathogenesis of cardiac death in these patients is not clear.
A 56-year-old Caucasian female patient presented with dyspnea and requested to donate her body to science in order to improve understanding of diffuse systemic sclerosis pathogenesis. She had extensive testing for dyspnea including pulmonary function tests, an echocardiogram, cardiac magnetic resonance imaging, and right heart catheterization to characterize her condition. Her case highlights the morbidity seen in this disease, including the presence of extensive skin thickening, digital ulcerations, and scleroderma renal crisis.
In this case report, we present the finding of cardiac tissue metabolomics, which may indicate a problem with vasodilation as a contributor to cardiac death in diffuse systemic sclerosis. The use of autopsy and tissue metabolomics in rare disease may help clarify disease pathogenesis.
Full-text · Article · Jun 2015 · Journal of Medical Case Reports
[Show abstract][Hide abstract] ABSTRACT: Background Calcinosis is a disabling, rarely discussed manifestation of SSc for which the natural history and management is poorly understood. This investigation is the 1st phase of a multi-tiered project to understand calcinosis from patients' perspectives creating the groundwork for a SSc-calcinosis PROM.
Methods Five focus groups and individual interviews in the US and UK were recorded and transcribed verbatim. Pathophysiologic and life impact were elicited with: 1. Since developing calcinosis how has your life changed over time? 2. How has calcinosis changed over time? A final probe was a request for questions that a clinician could ask to understand if calcinosis was better, worse or same.
Transcripts were analysed by hand (highest method) by an iterative inductive process (content drives coding) by at least 5 independent analysts including at least one patient research partner. Concepts were triangulated until a comprehensive set of concepts emerged. Occurrence was quantified per participant.
Results Twenty-three patients (29/31 female, 27/31 white, with mean disease duration 18.1 years) were consented and interviewed. Responses spanned broadly to include concepts of self-management strategies and recurrent hypotheses relating calcinosis development to trauma, Raynaud's and cold exposure (tables 1 & 2).
Cold exposure and Raynaud's were a perceived association to calcinosis severity - “when they are cold mine always open back up”.
A majority of patients engage in strategies to extrude calcinosis with either pressure +/- soaking or at home surgical techniques. “I actually have homemade surgical tools to get these out.”
The following anchors were consistently suggested for physicians to assess calcinosis severity: pain level, size, frequency, number and functional impairment. A 2-step question was suggested to help differentiate ulcer, infection and calcinosis symptoms: 1st regarding predomiant wound character and then target the related calcinosis.
Conclusions These results provide the groundwork for and conclude the 1st steps (item collection) in PROM development. As suggested by patients, a composite of scales anchored in pain, size, frequency, number and related impairment may reasonably serve as an interim instrument for SSc calcinosis. Next steps are validating content with a large subject base and questionniare development with subsequent validation.
Very importantly, patients' observations and self-management behavior provide opportunities to learn from and to preemptively educate physicians and patients. Patients are eager for self-management guidance. An essential deliverable of this work will be a patient-physician education guide on calcinosis management.
Acknowledgements In memory of Anne Mawdsley, founder: Raynaud's & Scleroderma Association UK – tireless engine for education and advocacy raising >£10 million for SSc research.
Disclosure of Interest A. Christensen: None declared, S. Khalique: None declared, S. Cenac: None declared, K. Fligelstone: None declared, V. Jaeger: None declared, A. Mawdsley: None declared, R. Kaufman: None declared, T. Frech: None declared, J. Gordon: None declared, V. Steen: None declared, A. Aubin: None declared, M. Baron: None declared, E. Busman: None declared, L. A. Saketkoo Grant/research support from: ACR/EULAR Exchange Awardee
No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
[Show abstract][Hide abstract] ABSTRACT: Background SSc is a complex, diffuse, devastating health condition of vascular injury, inflammation and fibrosis resulting in multiple organ involvement with high impact on survival and quality of life.
Demonstrated research activity tends to define SSc Centers of Excellence (SCoE) certification. However, SSc complications require coordinated high-level multi-specialty expert care. The Scleroderma Foundation, Scleroderma Australia and Scleroderma Society UK engaged SSc patients and SSc health providers (HPs) in a multi-tiered process to assess priorities in recognition of SCoEs.
Methods A mixed methods design ensured comprehensive item collection in addressing “important qualities and services in a certified SSc Center of Excellence”. A core of 35 patients & SSc HPs from 8 countries initiated the study through an iterative process using nominal group technique with rounds of item revision until saturation and satisfaction of proposed survey content was achieved and subsequently field-tested with a 5 point scale (critical to low importance).
Participation was screened and “gate-controlled” with online survey access through a unique one-time link. Telephone interview was offered. Responses from SSc patients and HPs were compared by Pearson's χ2 or Fisher's exact tests as appropriate.
Results Initial phases yielded a 54 item survey and field-tested in 15 SSc patients & HPs. 400 patients and SSc HPs received surveys of which 299 from 19 countries (75% response rate) were completers. Expert care superseded research as a priority of “critical importance” by HPs & patients respectively at 69% & 48% (p=0.02) and by 94% & 89% (p=0.8) when “critical to very important” were collapsed. 3 questions provided internal cross-validation of this query. “SCoEs should engage in research” received 57% of patients and 48% of HPs (p=0.37) as being critical. Further, education, rehabilitative services and support networks were consistently highly rated items with topics stratified by ratings (tables 1 & 2). Discrepant areas of importance between patients and HPs are highlighted in tables.
Conclusions Participation was robust in all project stages emphasizing the perceived global importance of this effort. Though research is of clear importance, quality expert care incorporating rehabilitative and educational provisions is a SCoE operational priority. These findings signal the need to redefine SCoE certification standards and provide a roadmap to SCoE development.
Acknowledgements Dedicated to the memory of Anne Mawdsley.
Disclosure of Interest V. Jaeger: None declared, A. Aubin: None declared, N. Baldwin: None declared, K. Fligelstone: None declared, R. Sims: None declared, J. Welling: None declared, R. Burrill: None declared, K. Connolly: None declared, J. Gordon: None declared, T. Frech: None declared, T. Ngcozana: None declared, M. Kowalczyk: None declared, M. Lammi: None declared, J. Lasky: None declared, U. Walker: None declared, L. A. Saketkoo Grant/research support from: ACR/EULAR Exchange Awardee
No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
[Show abstract][Hide abstract] ABSTRACT: Background Systemic sclerosis (SSc) is a family of diseases unified by the presence of immune activation, vasculopathy and fibrosis. The concept of SSc subsets cannot be easily defined but is clinically indisputable.
Objectives To evaluate the purpose, strengths and limitations of the limited/diffuse subset criteria, and identify areas requiring improvement.
Methods We conducted a cross-sectional study with 30 SSc experts using a semi-structured interview. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. This was followed by serial cross-referential analyses establishing a set of pervasive complex thought clusters.
Results Of the 30 experts, 26 (87%) were male, 19 (63%) were from Europe and 11 (37%) were from North America. The experts had seen SSc patients for a mean 23 (SD 10.7) years, and saw a mean of 122 (SD 185) new SSc patients annually. Three thematic clusters were noted regarding the utility of subsetting: to facilitate research and communication, to inform management, and to inform prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system has “little or no value”. Limitations of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold is arbitrary. 87% use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody determined subsets, subsetting based on speed of progression, and age of onset (juvenile, elderly). Considerations for the next phase of criteria development include incorporation of rate of change and hierarchal clustering (limited/diffuse, then by antibodies).
Conclusions We interviewed international SSc experts and synthesized their views on subset criteria. These results can inform future efforts to develop revised criteria to guide research, prognostication and management.
Acknowledgements This work was supported by the World Scleroderma Foundation.
Disclosure of Interest S. Johnson Grant/research support from: Canadian Institutes of Health Research, J. Fransen: None declared, D. Khanna Grant/research support from: NIH/NIAMS K24, F. van den Hoogen: None declared, M. Baron: None declared, M. Matucci-Cerinic: None declared, C. Denton: None declared, T. Medsger: None declared, P. Carreira: None declared, G. Riemekasten: None declared, J. Distler: None declared, A. Gabrielli: None declared, V. Steen: None declared, L. Chung: None declared, R. Silver: None declared, J. Varga: None declared, U. Muller-Ladner Grant/research support from: EULAR/EUSTAR and FP7 Desscipher, M. Vonk: None declared, U. Walker: None declared, F. Wollheim: None declared, A. Herrick: None declared, D. Furst: None declared, L. Czirjak: None declared, O. Kowal-Bielecka: None declared, F. DelGaldo: None declared, M. Cutolo: None declared, N. Hunzelmann: None declared, C. Murray: None declared, I. Foeldvari: None declared, L. Mouthon: None declared, N. Damjanov: None declared, B. Kahaleh: None declared, T. Frech: None declared, S. Assassi: None declared, L. A. Saketkoo: None declared, J. Pope: None declared
No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
[Show abstract][Hide abstract] ABSTRACT: Systemic sclerosis (SSc) vasculopathy can result in a digital ulcer (DU) and/or pulmonary arterial hypertension (PAH). We hypothesized that bedside brachial artery flow-mediated dilation (FMD) testing with duplex ultrasound could be used in SSc patients to identify features of patients at risk for DU or PAH. Thirty-eight SSc patients were compared to 52 age-matched healthy controls from the VAMC Utah Vascular Research Laboratory. Peripheral hemodynamics, arterial structure, and endothelial function were assessed by duplex ultrasound. A blood pressure cuff was applied to the forearm and 5-min ischemia was induced. Post-occlusion, brachial artery vascular reactivity (peak hyperemia/area under the curve [AUC]), shear rate, and endothelial function (FMD) were measured. SSc patients had smaller brachial artery diameters (p p p = 0.03), and brachial artery FMD (p p SSc patients with DU. Tertile analysis suggested the 2 lower FMD tertiles (SSc patients with highest FMD tertile (>5.40 %) had less than 15 % chance of DU. All brachial artery FMD measurements were similar between SSc patients with and without PAH (all p > 0.05). Compared to healthy controls, SSc patients had significantly smaller brachial artery diameter and blunted peripheral vascular reactivity and endothelial function. SSc patients with DU have even greater impairments in endothelial function compared to those without DU. FMD testing has clinical utility to identify SSc patients at risk for DU.
No preview · Article · Dec 2014 · Clinical Rheumatology
[Show abstract][Hide abstract] ABSTRACT: Objectives:
We sought to examine the relationship between measures of ILD severity and PH in patients with SSc.
We identified 55 subjects from 12 PHAROS sites with RHC-proven PH and HRCT evidence of ILD. Subjects with PH due to left heart disease were excluded. Baseline HRCT scans were scored by a standardised system that graded severity of ILD. Summary statistics were generated for baseline characteristics. Spearman correlation and linear regression were used to examine relationships between ILD and PH severity variables.
The majority of subjects were white women; nearly half had limited cutaneous SSc. Most subjects were New York Heart Association functional class II or III. Pulmonary function testing revealed moderate restriction (mean FVC 64.3 ± 17.2% predicted) with severe reduction in diffusing capacity (mean DLco 34.2 ± 13.3% predicted). RHC demonstrated mild to moderate PH (mean PAP 35 ± 9 mmHg, mean PVR 5.1 ± 3.7 WU). There was no correlation between severity of ILD (by either HRCT or PFT) and cardiac haemodynamic parameters of PH.
No association between severity of ILD and cardiac haemodynamic profiles were identified in this cohort. We believe this underscores the complex nature of PH and ILD in individuals with SSc. We do suspect that some individuals with SSc-ILD will also have concomitant pulmonary vascular disease but simple assessments to grade severity of ILD - by PFT or HRCT estimates of ILD extent - are likely not enough to reliably distinguish between PAH versus PH-ILD. Further research into how to distinguish and manage these subsets is warranted.
No preview · Article · Nov 2014 · Clinical and experimental rheumatology
[Show abstract][Hide abstract] ABSTRACT: Background
Electronic medical records (EMR) provide an ideal opportunity for the detection, diagnosis, and management of systemic sclerosis (SSc) patients within the Veterans Health Administration (VHA). The objective of this project was to use informatics to identify potential SSc patients in the VHA that were on prednisone, in order to inform an outreach project to prevent scleroderma renal crisis (SRC).
The electronic medical data for this study came from Veterans Informatics and Computing Infrastructure (VINCI). For natural language processing (NLP) analysis, a set of retrieval criteria was developed for documents expected to have a high correlation to SSc. The two annotators reviewed the ratings to assemble a single adjudicated set of ratings, from which a support vector machine (SVM) based document classifier was trained. Any patient having at least one document positively classified for SSc was considered positive for SSc and the use of prednisone>10 mg in the clinical document was reviewed to determine whether it was an active medication on the prescription list.
In the VHA, there were 4,272 patients that have a diagnosis of SSc determined by the presence of an ICD-9 code. From these patients, 1,118 patients (21%) had the use of prednisone>10 mg. Of these patients, 26 had a concurrent diagnosis of hypertension, thus these patients should not be on prednisone. By the use of natural language processing (NLP) an additional 16,522 patients were identified as possible SSc, highlighting that cases of SSc in the VHA may exist that are unidentified by ICD-9. A 10-fold cross validation of the classifier resulted in a precision (positive predictive value) of 0.814, recall (sensitivity) of 0.973, and f-measure of 0.873.
Our study demonstrated that current clinical practice in the VHA includes the potentially dangerous use of prednisone for veterans with SSc. This present study also suggests there may be many undetected cases of SSc and NLP can successfully identify these patients.
Full-text · Article · Oct 2014 · Computers in Biology and Medicine
[Show abstract][Hide abstract] ABSTRACT: Background Ischemic digital ulcers (DU) are a frequent complication in systemic sclerosis, estimated to occur in over 40% of patients. Treprostinil diethanolamine, a newer prostacyclin analog that has been developed for oral delivery, improves cutaneous perfusion and temperature in scleroderma patients. A large randomized, double-blind, placebo-controlled clinical trial of treprostinil diethanolamine was conducted in scleroderma patients with DU (ClinicalTrials.gov identifier NCT00775463). While this trial did not meet the desired endpoint (change in net ulcer burden at 20 wks), there was a significant improvement in several secondary endpoints that measured Raynaud's severity. Subjects enrolled into an open label extension study (DISTOL-EXT) after the clinical trial, and after termination of DISTOL-EXT, all participants were withdrawn from oral treprostinil.
Objectives We investigated whether active, indeterminate, and total ulcer burden increased in DISTOL-EXT participants after they discontinued oral treprostinil.
Methods In this multi-center, retrospective study, medical records for the year after discontinuation of treprostinil were reviewed. Data from these routine clinical visits were abstracted into a template designed a priori to capture information on the number of active and indeterminate DU at the end of the extension study and at subsequent visits. Participants who did not have a subsequent visit with documentation of DU status were excluded from this study. We examined the number of new DU that developed from the end of the extension study (baseline) through the first year after discontinuation of treprostinil. The number of active, indeterminate and total DU 3-6 months (time A) and >6-12 months (time B) after discontinuation of treprostinil were compared to baseline by the paired t-test.
Results Fifty-one subjects from 9 SSc Centers were included for analysis. At the conclusion of the treprostinil extension study, the mean number of active, indeterminate and total DU was 0.25 (SD 0.63), 0.22 (SD 0.54) and 0.47 (SD 0.78), respectively. The number of active DU increased from baseline to time A (mean 1.62, p=0.004, N=23) and time B (mean 1.03, p=0.076, N=30). The number of indeterminate DU increased from baseline to time B (mean 0.42, p=0.03, N=30) but not time A. The total DU burden increased significantly from baseline to time A (mean 2.1, p=0.002, N=23) and time B (mean 1.45, p=0.01, N=30) as shown in the Figure. The majority of patients required intensive vasodilator therapy and pain medication: calcium channel blockers (60.8%), PDE 5 inhibitors (21.6%), any pain medication (58.8%), opioids (33.3%). Three patients were hospitalized for complications from digital ulcers, and four patients required surgical intervention. Five patients were subsequently diagnosed with pulmonary hypertension.
Conclusions Total DU burden increased significantly after discontinuation of oral treprostinil diethanolamine. These data provide supportive evidence of a beneficial effect of oral treprostinil diethanolamine for the vascular complications of SSc.
Disclosure of Interest A. Shah Grant/research support: United Therapeutics, E. Schiopu Grant/research support: United Therapeutics, Actelion, MedImmune, Celgene, Speakers bureau: Previously on United Therapeutics Speakers bureau, S. Chatterjee Grant/research support: United Therapeutics, M. E. Csuka Grant/research support: United Therapeutics, T. Frech Grant/research support: United Therapeutics, A. Goldberg Grant/research support: United Therapeutics, R. Spiera Grant/research support: United Therapeutics, S. Peng Grant/research support: United Therapeutics, V. Steen Grant/research support: United Therapeutics
No preview · Article · Jun 2014 · Annals of the Rheumatic Diseases
[Show abstract][Hide abstract] ABSTRACT: Objective
To examine parental influence on the development of systemic sclerosis (SSc; scleroderma). We designed 3 studies: mitochondrial inheritance, birth order (a possible surrogate marker for microchimerism), and paternal age at conception (a possible surrogate for telomere erosion) to examine their association with development of SSc.MethodsSSc was defined by International Classification of Diseases, Ninth and Tenth Revision codes (ICD-9 710.1 and ICD 10 M34.0, M34.1, and M34.9) and identified from statewide discharge data, University of Utah Health Science Center Enterprise Data Warehouse (UUHSC), and death certificates that were linked to the Utah Population Database (UPDB) for analysis. Mitochondrial inheritance was evaluated by conditional logistic regression and population attributable risk using familial standardized incidence ratio as the covariate. Chi-square test and logistic regression were used to evaluate birth order and maternal/paternal age at conception of the SSc proband.ResultsWe found 1,947 unique SSc patients from UUHSC and UPDB. We selected 5 controls per case (n = 9,115), matched by birth year and sex. Mitochondrial inheritance analysis indicated no evidence to suggest SSc was associated with mitochondrial inheritance. Birth order and maternal/paternal age at conception analysis results show that they also do not significantly affect SSc development.Conclusion
Results suggest that although heritable risk of SSc is observed, mitochondrial inheritance, birth order, and parental age are not likely responsible for pathogenesis.
[Show abstract][Hide abstract] ABSTRACT: Objective
To assess cumulative survival rates and identify independent predictors of mortality in patients with incident systemic sclerosis (SSc)–associated pulmonary arterial hypertension (PAH) who had undergone routine screening for PAH at SSc centers in the US. Methods
The Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma registry is a prospective registry of SSc patients at high risk for PAH or with definite pulmonary hypertension diagnosed by right-sided heart catheterization within 6 months of enrollment. Only patients with World Health Organization group I PAH (mean pulmonary artery pressure ≥25 mm Hg and pulmonary capillary wedge pressure ≤15 mm Hg without significant interstitial lung disease) were included in these analyses. ResultsIn total, 131 SSc patients with incident PAH were followed for a mean ± SD of 2.0 ± 1.4 years. The 1-, 2-, and 3-year cumulative survival rates were 93%, 88%, and 75%, respectively. On multivariate analysis, age >60 years (hazard ratio [HR] 3.0, 95% confidence interval [95% CI] 1.1–8.4), male sex (HR 3.9, 95% CI 1.1–13.9), functional class (FC) IV status (HR 6.5, 95% CI 1.8–22.8), and diffusing capacity for carbon monoxide (DLco) <39% predicted (HR 4.2, 95% CI 1.3–13.8) were significant predictors of mortality. Conclusion
This is the largest study describing survival in patients with incident SSc-associated PAH followed up at multiple SSc centers in the US who had undergone routine screening for PAH. The survival rates were better than those reported in other recently described SSc-associated PAH cohorts. Severely reduced DLco and FC IV status at the time of PAH diagnosis portended a poor prognosis in these patients.
[Show abstract][Hide abstract] ABSTRACT: Type I interferons (IFNs) are implicated in the pathogenesis of systemic sclerosis (SSc). MEDI-546 is an investigational human monoclonal antibody directed against the type I IFN receptor. This Phase 1 study evaluated the safety/tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of single and multiple intravenous doses of MEDI-546 in adults with SSc.
Subjects (>=18 years) with SSc were enrolled in an open-label, dose-escalation study to receive single (0.1, 0.3, 1.0, 3.0, 10.0, or 20.0 mg/kg), or 4 weekly intravenous doses (0.3, 1.0, or 5.0 mg/kg/week) of MEDI-546. Subjects were followed for 12 weeks. Safety assessments included adverse events (AEs), laboratory results, and viral monitoring. Blood samples were collected from all subjects for determination of PK, presence of anti-drug antibodies (ADAs), and expression of type I IFN-inducible genes.
Of 34 subjects (mean age 47.4 years), 32 completed treatment and 33 completed the study. Overall, 148 treatment-emergent AEs (TEAEs) were reported (68.9% mild, 27.7% moderate). TEAEs included one grade 1 infusion reaction (5.0 mg/kg/week multiple dose). Of 4 treatment-emergent serious AEs (skin ulcer, osteomyelitis, vertigo, and chronic myelogenous leukemia (CML)), only CML (1.0 mg/kg/week multiple dose) was considered possibly treatment-related. MEDI-546 exhibited non-linear PK at lower doses. ADAs were detected in 5 subjects; no apparent impact on PK was observed. Peak inhibition of the type I IFN signature in whole blood was achieved within 1 day and in skin after 7 days.
The safety/tolerability, PK, and PD profiles observed in this study support further clinical development of MEDI-546.Trial Registration: ClinicalTrials.gov NCT00930683.
Full-text · Article · Feb 2014 · Arthritis research & therapy
[Show abstract][Hide abstract] ABSTRACT: Interstitial lung diseases (ILD), including those related to connective tissue disease (CTD), and idiopathic pulmonary fibrosis (IPF) carry high morbidity and mortality. Great efforts are under way to develop and investigate meaningful treatments in the context of clinical trials. However, efforts have been challenged by a lack of validated outcome measures and by inconsistent use of measures in clinical trials. Lack of consensus has fragmented effective use of strategies in CTD-ILD and IPF, with a history of resultant difficulties in obtaining agency approval of treatment interventions. Until recently, the patient perspective to determine domains and outcome measures in CTD-ILD and IPF had never been applied. Efforts described here demonstrate unequivocally the value and influence of patient involvement on core set development. Regarding CTD-ILD, this is the first OMERACT working group to directly address a manifestation/comorbidity of a rheumatic disease (ILD) as well as a disease not considered rheumatic (IPF). The OMERACT 11 proceedings of the CTD-ILD Working Group describe the forward and lateral process to include both the medical and patient perspectives in the urgently needed identification of a core set of preliminary domains and outcome measures in CTD-ILD and IPF.
Full-text · Article · Feb 2014 · The Journal of Rheumatology