[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.
[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.
Current Respiratory Medicine Reviews 06/2015; 11(999):1-1. DOI:10.2174/1573398X11666150619183704
[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.
Journal of Medical Case Reports 06/2015; 9(1):136. DOI:10.1186/s13256-015-0587-7
[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
Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):600.1-600. DOI:10.1136/annrheumdis-2015-eular.2569 · 10.38 Impact Factor
[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
Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):1135.3-1136. DOI:10.1136/annrheumdis-2015-eular.2528 · 10.38 Impact Factor
[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.
[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.
[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.
Computers in Biology and Medicine 10/2014; 53. DOI:10.1016/j.compbiomed.2014.07.022 · 1.24 Impact Factor
[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.
[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.
The Journal of Rheumatology 02/2014; 41(4). DOI:10.3899/jrheum.131251 · 3.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Systemic sclerosis (SSc) has the potential to result in irreversible damage in various organs.
Objectives To determine the accrual of damage in each organ system in the first five years of SSc disease.
Methods A panel of experts defined organ-specific indicators of damage in SSc. Using prospectively acquired data from patients entering the Australian Scleroderma Cohort Study within 2 years of disease onset, annual accrual of organ damage from years 2 to 5 following disease onset was determined.
Results The frequency of each damage indicator at years 2 to 5 in 182 patients is presented in the graph. Damage occurred in all organ systems, most commonly in the skin/MSK (23.1% at 4 years), respiratory (12.1%), GI (7.1%) & GU systems (erectile dysfunction in men 31.4%).
Conclusions Organ damage occurs early in SSc. This is a compelling rationale for forming a large inception cohort (INternational SYstemic Sclerosis Inception Cohort; INSYNC) of patients with SSc to determine the predictors of organ damage and to develop strategies for preventing the occurrence of organ damage in SSc.
Disclosure of Interest None Declared
Annals of the Rheumatic Diseases 01/2014; 72(Suppl 3):A499-A499. DOI:10.1136/annrheumdis-2013-eular.1499 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, pro- vided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.
The American Journal of Human Genetics 01/2014; 94(1):47-61. DOI:10.1016/j.ajhg.2013.12.002. · 10.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities.
The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology-a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF).
A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed.
Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.
[Show abstract][Hide abstract] ABSTRACT: Gastrointestinal tract (GIT) involvement in systemic sclerosis (scleroderma, SSc) is the most common internal complication. This review discusses the outcome measures to capture GIT involvement in clinical care and trials.
Patient-reported outcome measures have been validated (UCLA Scleroderma Clinical Trial Consortium GIT 2.0 and NIH PROMIS scales) in SSc-GIT. Multiple objective measures are available to assess mucosal involvement and motility in GIT. However, these need to be validated in SSc for trials.
GIT is a common cause of morbidity and has negative impact on quality of life in SSc. Recommendations are given for trial design and evaluation of GIT involvement in SSc.
Current opinion in rheumatology 09/2013; 25(6). DOI:10.1097/01.bor.0000434668.32150.e5 · 4.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Autophagosomes are formed during autophagy, which is activated by hypoxia and starvation. Autophagy is important for mast cell degranulation. We hypothesized that autophagy is a key feature in the pathogenesis of systemic sclerosis (SSc). We examined SSc clinical features and mast cell density across the presence and severity of autophagy. Skin punch biopsy was performed on 33 SSc patients and 6 healthy controls (HC). Autophagy was evaluated by immunofluorescence on paraffin sections using LC3-FITC staining on these patients. The intensity of staining and mast cell density was examined across clinical features in 19 of the SSc patients. Presence of autophagosome formation was assessed by EM in 17 of the SSc patients and 4 HC. In our SSc study population, 29 of subjects were female and 23 were limited cutaneous. Twenty-nine of 33 SSc patients had autophagy by LC3-FITC staining. Intensity of staining decreased with longer duration of SSc (p = 0.09) and RP (p = 0.10). Bloating and distention differed across level of intensity staining (Wilcoxon signed-rank test, p = 0.05), with the greatest levels among those with moderate intensity. On EM, autophagosome formation was present in 16 of 17 SSc patients and no HC. All SSc patients had perivascular mast cells. Autophagy was present in 29 of 33 SSc patients, and none of our HC suggesting importance in pathogenesis. Autophagy staining was greater among those with shorter duration of SSc. Bloating and distention were higher in patients with moderate autophagy staining. Perivascular mast cells were present in all SSc patients. The role of autophagy in vasculopathy and mast cell activation in SSc warrants further studies.
Rheumatology International 08/2013; 34(3). DOI:10.1007/s00296-013-2827-8 · 1.52 Impact Factor