Circulating angiopoietin and Tie-2 levels in systemic sclerosis.

To determine the potential effects of angiopoietins Ang-1 and Ang-2 and their receptor Tie-2 in patients with systemic sclerosis (SSc). Twenty-six patients with limited SSc (l-SSc) and fourteen patients with diffuse SSc (d-SSc) were evaluated and compared to age-matched controls. Plasma levels of soluble sAng-1, sAng-2, sTie-2, vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and endostatin were measured. Associations between these factors and clinical parameters were assessed. Levels of circulating factors and the ratios sAng-2/sAng-1 and sAng-2/sTie-2 were not different between l-SSc and d-SSc cases but were collectively higher compared to their controls: sAng-1 (p = 0.0108); sAng-2 (p < 0.0001); sTie-2 (p < 0.0001); endostatin (p < 0.0001), PlGF (p < 0.0001); VEGF (p = 0.0006); sAng-2/sAng-1 (p < 0.0001); sAng-2/sTie-2 (p < 0.0001). Concerning significant correlations among the angiopoietins and Tie-2, sAng-2 associated with sTie-2 (Spearman r = 0.47, p = 0.0155) in l-SSc only. sAng-1 did not show statistically significant correlations with any of the clinical variables, but sAng-2 did between PAP (r = 0.51, p = 0.0148) and predicted DLCO (r = -0.31, p = 0.0242) in l-SSc cases. sTie-2 negatively correlated with disease duration in l-SSc (r = -0.55, p = 0.0049). The sAng-2/sTie-2 ratio shows a positive association with disease activity in both l-SSc (r = 0.50, p = 0.0547) and d-SSc (r = 0.60, p = 0.0317). Levels of sAng-1, sAng-2 and sTie-2 are higher in SSc cases suggesting a pro-inflammatory state in an active endothelium. The near doubling of the sAng-2/sTie-2 ratio in SSc cases compared to controls suggests a shift toward vascular regression and angiostasis perhaps caused by Ang-2 blocking the action of Tie-2.

Circulating cytokine levels in systemic sclerosis related interstitial lung disease and idiopathic pulmonary fibrosis.

Exploration of cytokine levels in systemic sclerosis-associated interstitial lung disease (SSc-ILD) and idiopathic pulmonary fibrosis (IPF) is needed to find common and diverse biomolecular pathways. Circulating levels of 87 cytokines were compared amongst 19 healthy controls and consecutive patients with SSc-ILD (n = 39), SSc without ILD (n = 29), and IPF (n = 17) recruited from a Canadian centre using a log-linear model adjusted for age, sex, baseline forced vital capacity (FVC), and immunosuppressive or anti-fibrotic treatment at time of sampling. Also examined was annualized change in FVC. Four cytokines had Holm's corrected p-values less than 0.05. Eotaxin-1 levels were increased approximately two-fold in all patient categories compared to healthy controls. Interleukin-6 levels were eight-fold higher in all ILD categories compared to healthy controls. MIG/CXCL9 levels increased two-fold more in all but one patient category compared to healthy controls. Levels of a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13, (ADAMTS13) were lower for all categories of patients compared to controls. No substantial association was found for any of the cytokines with FVC change. Observed cytokine differences suggest both common and diverse pathways leading to pulmonary fibrosis. Further studies evaluating longitudinal change of these molecules would be informative.

International Classification of Functioning, Disability and Health Core Set construction in systemic sclerosis and other rheumatic diseases: a EUSTAR initiative.

OBJECTIVES: To outline rationale and potential strategies for rheumatology experts to be able to develop disease-specific Core Sets under the framework of the International Classification of Functioning, Disability and Health (ICF). ICF is a universal framework introduced by the World Health Organization (WHO) to describe and quantify the impact and burden on functioning of health conditions associated with impairment/disability. METHODS: A combined effort of the EULAR Scleroderma Clinical Trial and Research and the ICF Research Branch was initiated to develop an ICF language for scleroderma. From our Medline literature review, using the abbreviation and spelled out version of ICF, we assembled approaches and methodological reasoning for steps of core set development. RESULTS: The ICF can be used for patient care and policy-making, as well as the provision of resources, services and funding. The ICF is used on institutional, regional, national and global levels. Several diseases now have ICF Core Sets. Patients with complex rheumatologic diseases will benefit from a disease-specific ICF Core Set and should be included in all stages of development. ICF Core Set development for rheumatic diseases can be conducted from a number of feasible strategies. CONCLUSION: This overview should help to clarify useful processes leading to development of an ICF Core Set, and also provide a platform for expert groups considering such an endeavour.

The effect of injection immunotherapy on mucociliary clearance in allergic patients.

OBJECTIVE: To assess the effect of injection immunotherapy on mucociliary clearance in allergic patients with the use of the saccharin test. METHODS: In this prospective cohort study, mucociliary clearance in 42 allergic patients treated with injection immunotherapy was determined with the saccharin test. Of these patients, 23 were retested 1 year later to assess changes in mucociliary clearance times. Mean results for historical controls were determined in a review and meta-analysis of the existing literature. RESULTS: Saccharin clearance times (SCTs) were initially prolonged in allergic patients who received injection immunotherapy when compared to historical controls (one-sided P value < 0.05). However, after 1 year of immunotherapy, there was a significant reduction in SCTs in our patient population. This finding was independent of other evaluated patient characteristics, with the exception of nasal steroid use, which was also significantly associated with a decrease in SCT. CONCLUSIONS: After 1 year of injection immunotherapy, there was a significant reduction in mean SCT in our patient population. Of the other factors studied, only nasal steroid was associated with decreased mucociliary clearance times. To our knowledge, this is the first report in the literature documenting the beneficial effect of injection immunotherapy on mucociliary clearance as measured by saccharin clearance times. Nevertheless, further research is warranted, given the confounding effect of nasal steroid use.

2014 Update of the Canadian Rheumatology Association/Spondyloarthritis Research Consortium of Canada Treatment Recommendations for the Management of Spondyloarthritis. Part II: Specific Management Recommendations.

OBJECTIVE: The Canadian Rheumatology Association (CRA) and the Spondyloarthritis Research Consortium of Canada (SPARCC) have collaborated to update the recommendations for the management of spondyloarthritis (SpA). METHODS: A working group was assembled and consisted of the SPARCC executive committee, rheumatologist leaders from SPARCC collaborating sites, Canadian rheumatologists from across the country with an interest in SpA (both academic and community), a rheumatology trainee with an interest in SpA, an epidemiologist/health services researcher, a member of the CRA executive, a member of the CRA therapeutics committee, and a patient representative from the Canadian Spondylitis Association. An extensive review was conducted of literature published from 2007 to 2014 involving the management of SpA. The working group created draft recommendations using multiple rounds of Web-based surveys and an in-person conference. RESULTS: Recommendations for the management of SpA were created. Part II: Specific Management Recommendations addresses management with nonpharmacologic methods, nonsteroidal anti-inflammatories and analgesics, disease-modifying antirheumatic drugs, antibiotics, tumor necrosis factor inhibitors, other biologic agents, and surgery. Also included are 10 modifications for application to juvenile SpA. CONCLUSION: These recommendations were developed based on current literature and applied to a Canadian healthcare context. It is hoped that implementation of these recommendations will promote best practices in the treatment of SpA.

2014 Update of the Canadian Rheumatology Association/spondyloarthritis research consortium of Canada treatment recommendations for the management of spondyloarthritis. Part I: principles of the management of spondyloarthritis in Canada.

OBJECTIVE: The Canadian Rheumatology Association (CRA) and the Spondyloarthritis Research Consortium of Canada (SPARCC) have collaborated to update the recommendations for the management of spondyloarthritis (SpA). METHODS: A working group was assembled and consisted of the SPARCC executive committee, rheumatologist leaders from SPARCC collaborating sites, Canadian rheumatologists from across the country with an interest in SpA (both academic and community), a rheumatology trainee with an interest in SpA, an epidemiologist/health services researcher, a member of the CRA executive, a member of the CRA therapeutics committee, and a patient representative from the Canadian Spondylitis Association. An extensive review was conducted of literature published from 2007 to 2014 involving the management of SpA. The working group created draft recommendations using multiple rounds of Web-based surveys and an in-person conference. A survey was sent to the membership of the CRA to obtain an extended review that was used to finalize the recommendations. RESULTS: Guidelines for the management of SpA were created. Part I focuses on the principles of management of SpA in Canada and includes 6 general management principles, 5 ethical considerations, target groups for treatment recommendations, 2 wait time recommendations, and recommendations for disease monitoring. Also included are 6 modifications for application to juvenile SpA. CONCLUSION: These recommendations were developed based on current literature and applied to a Canadian healthcare context. It is hoped that the implementation of these recommendations will promote best practices in the treatment of SpA.

Genome-wide linkage analysis of the tracking of systolic blood pressure using a mixed model.

BACKGROUND: Elevated blood pressure in middle age is a major risk factor for subsequent cardiovascular complications. An important longitudinal characteristic of blood pressure is the "tracking phenomenon". Tracking is defined as the persistence of the rank of a person's blood pressure level in a group over a long period of time. In this analysis, we used the Framingham data to investigate whether there are some genes responsible for this phenomenon. RESULTS: Both two-point and multipoint linkage analyses were applied to family members with complete data only and to all family data with missing values imputed by a Gaussian model. The results of two-point linkage analysis indicated that two loci for linkage with the intercept were on chromosomes 10 and 13, and two loci for linkage with both slope and intercept were on chromosomes 1 and 3. Multipoint linkage analysis indicated only one region, 200-240 cM on chromosome 1, to be linked with both intercept and slope. For the intercept of SBP, the highest LOD (4.43) was found at 214 cM when missing data were imputed, and the highest LOD (2.81) was at 231 cM for the complete case data. For the slope of SBP, the highest multipoint LODs were 3.63 at 227 cM and 2.02 at 234 cM for the complete case data and imputation data, respectively. CONCLUSION: One or more genes in the range of 200-240 cM on chromosome 1 may be related to the tracking phenomenon of SBP.

The role of sequential and concurrent sexual relationships in the risk of sexually transmitted diseases among adolescents.

PURPOSE: To explore whether patterns of sexual relationships, such as sequential (nonoverlapping in time) or concurrent (overlapping in time), are more important indicators of sexually transmitted disease (STD) risk among adolescents than number of sexual partners. METHODS: Data from 4,707 sexually active adolescents from the National Longitudinal Study of Adolescent Health were analyzed based on reported heterosexual relationships during the past 18 months. Adolescents were categorized as engaging in single, sequential, or concurrent sexual relationships. Demographic, behavioral, and social characteristics of each group were compared and multivariate logistic models were fit to determine STD risk associated with sexual relationship patterns and overall number of sexual partners during this same time period. RESULTS: Thirty-five percent of sexually active teens had more than one partner in the past 18 months, and 40% of these multiple partnerships were overlapping or concurrent in time. Teens in sequential and concurrent relationships reported lower condom use and a higher degree of regret of having sex owing to alcohol use than those in single relationships. Teens in concurrent relationships also reported the lowest self-efficacy to use contraceptives. Teens in sequential or concurrent relationships were more likely to report an STD than single-relationship teens (odds ratio 2.3 and 3.9, respectively); however, they were not statistically different from each other. Number of sexual partners during this same time period was not associated with STD risk once relationship pattern was considered. CONCLUSIONS: Adolescents who engage in sequential or concurrent sexual relationships differ in some important demographic, behavioral, and social characteristics and, when compared with those who engage in single relationships, have a significantly greater risk for STDs over and above the number of sexual partners.

Prevalence of allergy in patients with chronic rhinosinusitis.

OBJECTIVES: The purpose of this study was to provide further evidence that allergic rhinitis is an important factor in chronic and recurrent acute rhinosinusitis. Specifically, this study shows that perennial allergens play a more significant role than seasonal allergens. STUDY DESIGN AND SETTING: Census by chart review of patients with chronic and recurrent acute rhinosinusitis presenting to the Department of Otolaryngology at the MetroHealth Medical Center, Cleveland, OH. METHODS: All participants had allergy testing done either by RAST or intradermal skin endpoint titration utilizing a battery of seasonal and perennial antigens. RESULTS: Of the 48 voluntary participants analyzed in this study, 57.4% had a positive allergy test. Most patients in the study were sensitive to more than one allergen. Of the patients with a positive allergy test, 92% demonstrated sensitivity to one or more perennial allergens-most prominently, molds and dust mites. CONCLUSIONS: Perennial allergy has a statistically significant association with chronic and recurrent acute rhinosinusitis. SIGNIFICANCE: The diagnosis and management of perennial allergies may be beneficial when treating chronic sinus disease.

Systematic Review of the Role of Microparticles in Systemic Sclerosis.

Microparticles (MPs) are small, membrane-coated vesicles released in response to injury, cell activation or apoptosis. Growing evidence suggests associations between MPs and disease manifestations in systemic sclerosis (SSc). The aim of this study is to systematically review published articles and abstracts that discuss the role of MPs in SSc. The Web of Science(®), PubMed(®) and Google Scholar databases were searched for all articles and abstracts that discussed MPs in the context of SSc. The literature search was conducted on 18 July 2013 and restricted to English-language articles and abstracts. From a total of 150 distinct articles and 10 abstracts, only 14 articles and 4 abstracts met the criteria for an attempt of quantitative synthesis. Twenty articles were accepted for a review of reviews. Conference proceedings and journals not cataloged in either Web of Science(®) or PubMed(®) or searchable by Google Scholar would have been undetected. There is a risk of valid studies with negative results going unpublished. Few studies have been conducted on MPs in patients with SSc so it was possible to thoroughly consider each. While there is low quality evidence from studies that plasma concentrations of circulating endothelial and platelet MPs are elevated in SSc patients and that plasma concentrations of circulating endothelial MPs are higher in SSc cases with either pulmonary hypertension or interstitial lung disease than those SSc cases without, definitive conclusions are not possible due to heterogeneity of the studies with respect to inclusion criteria, populations studied, laboratory analysis methods, and choice of outcome statistics.

L-selectin and skin damage in systemic sclerosis.

BACKGROUND: L-selectin ligands are induced on the endothelium of inflammatory sites. L-selectin expression on neutrophils and monocytes may mediate the primary adhesion of these cells at sites of inflammation by mediating the leukocyte-leukocyte interactions that facilitate their recruitment. L-selectin retains functional activity in its soluble form. Levels of soluble L-selectin have been reported as both elevated and lowered in patients with systemic sclerosis (SSc). This preliminary study seeks to discern amongst these disparate results and to discover whether there is an association between L-selectin concentrations in plasma and skin damage in SSc patients. METHODOLOGY AND PRINCIPAL FINDINGS: Nineteen cases with limited systemic sclerosis (lSSc) and 11 cases with diffuse systemic sclerosis (dSSc) were compared on a pairwise basis to age- and sex-matched controls. Criteria of the American College of Rheumatology were used to diagnose SSc. Skin involvement was assessed using the modified Rodnan skin score (mRSS). We find no association between mRSS and plasma L-selectin concentration in lSSc cases (p = 0.9944) but a statistically significant negative correlation in dSSc cases (R(2) = 73.11 per cent, p = 0.0008). The interpretation of the slope for dSSc cases is that for each increase of 100 ng/ml in soluble L-selectin concentration, the mRSS drops 4.22 (95 per cent CI: 2.29, 6.16). There was also a highly statistically significant negative correlation between sL-selectin and disease activity (p = 0.0007) and severity (p = 0.0007) in dSSc cases but not in lSSc cases (p = 0.2596, p = 0.7575, respectively). CONCLUSIONS AND SIGNIFICANCE: No effective treatments exist for skin damage in SSc patients. Nor is there a laboratory alternative to the modified Rodnan skin score as is the case for other organs within the body. Modulation of circulating L-selectin is a promising target for reducing skin damage in dSSc patients. Plasma levels of soluble L-selectin could serve as an outcome measure for dSSc patients in clinical trials.

The role of allergy and smoking in chronic rhinosinusitis and polyposis.

OBJECTIVES/HYPOTHESIS: The article considers the interrelatedness of allergic rhinitis and chronic rhinosinusitis (CRS). The negative impact of perennial allergy and tobacco use on polyposis in sinus surgery patients is explored. STUDY DESIGN: A retrospective chart review, performed by the first author over a 6-year period, of patients who underwent functional endoscopic sinus surgery for CRS. METHODS: The subjects' allergy status and smoking history are scrutinized by summary statistics and a multiple linear logistic model for predicting the presence of polyps. RESULTS: High prevalence of perennial allergic rhinitis (PAR) is seen in the subject population (56.4%). Both PAR and tobacco use are associated with nasal polyposis (P = .0073 and P = .0114, respectively). CONCLUSIONS: The close association of PAR and CRS suggests a possible causal link. Management of allergic rhinitis and tobacco cessation may provide greater control of chronic hyperplastic rhinosinusitis.

Analysis of metabolic syndrome phenotypes in Framingham Heart Study families from Genetic Analysis Workshop 13.

Twelve teams of investigators constituted a group which analyzed phenotypes related to metabolic syndrome, making use of the available longitudinal measurements from the family component of the Framingham Heart Study or the simulated data, as distributed by Genetic Analysis Workshop 13 (GAW13). Body mass index, obesity, lipid abnormalities, glucose, or combinations of these traits were analyzed by this group. A wide variety of approaches were taken to construct phenotypes from the longitudinal measurements, including considering single or multiple cross-sectional time points, single ages, minimum values, maximum values, means, other lifetime values, ever/never dichotomy, or age at onset of some threshold value. Approaches also differed in the family structures utilized (sib pairs to full extended pedigrees), the genetic data considered (two-point or multipoint), and the statistics calculated (model-free and parametric), and led to a diverse set of analyses being performed. Inferences were made about heritability, and attempts were made to map underlying genes. Over 40 genome-wide linkage analyses were conducted. Despite the broad range of approaches, several regions of the genome were repeatedly identified across multiple analyses.