Search

Greater literature on twice exceptionality has led to increased understanding and practical applications in supporting the success of students. However, much of the literature does not take into consideration the intersection of giftedness, disability, and cultural identities, which can significantly shape the experience of students in school. This chapter focuses on these intersecting identities through a case study of a gifted African American student with a learning disability. This case study illustrates both the challenges and strengths that this student faced in his K-12 educational pursuit. Further, the chapter offers practical solutions and strategies for teachers and school counselors to collaborate with families to promote student success.

BackgroundDespite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma.MethodsWe randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score.ResultsIn the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group.ConclusionsMyeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).

The transversity distribution, which describes transversely polarized quarks in transversely polarized nucleons, is a fundamental component of the spin structure of the nucleon, and is only loosely constrained by global fits to existing semi-inclusive deep inelastic scattering (SIDIS) data. In transversely polarized p↑+p collisions it can be accessed using transverse polarization dependent fragmentation functions which give rise to azimuthal correlations between the polarization of the struck parton and the final state scalar mesons.This letter reports on spin dependent di-hadron correlations measured by the STAR experiment. The new dataset corresponds to 25 pb−1 integrated luminosity of p↑+p collisions at s=500 GeV, an increase of more than a factor of ten compared to our previous measurement at s=200 GeV. Non-zero asymmetries sensitive to transversity are observed at a Q2 of several hundred GeV and are found to be consistent with the former measurement and a model calculation. We expect that these data will enable an extraction of transversity with comparable precision to current SIDIS datasets but at much higher momentum transfers where subleading effects are suppressed. Keywords: Transversity, Di-hadron correlations, Interference fragmentation function

ObjectiveValid measures of appearance concern are needed in systemic sclerosis (SSc), a rare, disfiguring autoimmune disease. The Derriford Appearance Scale-24 (DAS-24) assesses appearance-related distress related to visible differences. There is uncertainty regarding its factor structure, possibly due to its scoring method.DesignCross-sectional survey.SettingParticipants with SSc were recruited from 27 centres in Canada, the USA and the UK. Participants who self-identified as having visible differences were recruited from community and clinical settings in the UK.ParticipantsTwo samples were analysed (n=950 participants with SSc; n=1265 participants with visible differences).Primary and secondary outcome measuresThe DAS-24 factor structure was evaluated using two scoring methods. Convergent validity was evaluated with measures of social interaction anxiety, depression, fear of negative evaluation, social discomfort and dissatisfaction with appearance.ResultsWhen items marked by respondents as ‘not applicable’ were scored as 0, per standard DAS-24 scoring, a one-factor model fit poorly; when treated as missing data, the one-factor model fit well. Convergent validity analyses revealed strong correlations that were similar across scoring methods.ConclusionsTreating ‘not applicable’ responses as missing improved the measurement model, but did not substantively influence practical inferences that can be drawn from DAS-24 scores. Indications of item redundancy and poorly performing items suggest that the DAS-24 could be improved and potentially shortened.

Introduction: Individuals with visible differences due to medical conditions, such as systemic sclerosis (SSc; scleroderma), have reported difficulty navigating social situations because of issues such as staring, invasive questions, and rude comments. Fears or anxiety linked to situations in which a person interacts with others is known as social interaction anxiety. However, there exists no validated measurement tool to examine social interaction anxiety in rheumatologic conditions. Methods: The present study examines the reliability (internal consistency) and validity (structural and convergent) of the Social Interaction Anxiety Scale-6 (SIAS-6) in a sample of 802 individuals with SSc, and compares these psychometric properties across limited and diffuse subtypes of the disease. Multi-group confirmatory factor analysis was used to examine the factor structure of the SIAS-6 in patients with both limited and diffuse SSc. Results: A one-factor structure was found to fit well for individuals with SSc with both limited and diffuse disease. The measure demonstrated strong internal consistency reliability and convergent validity with relevant measures in expected magnitudes and directions. Conclusions: The SIAS-6 is a psychometrically robust measure that can confidently be used in SSc populations to examine social interaction anxiety. Moreover, scores can meaningfully be compared between patients with limited and diffuse disease., MD Anderson Cancer Center - University of Texas MD Anderson Cancer Center(undefined), Financial support: The Scleroderma Patient-centered Intervention Network (SPIN) is funded by a Canadian Institutes of Health Research (CIHR) Emerging Team Grant for Rare Diseases (PI, Thombs; TR3-119192). In addition to CIHR funding, SPIN has received institutional contributions from the Lady Davis Institute for Medical Research of the Jewish General Hospital, Montréal, Canada and from McGill University, Montréal, Canada. SPIN has also received support from the Scleroderma Society of Ontario, Scleroderma Canada, and Sclérodermie Québec. Ms. Gholizadeh’s work on this project was supported by a Rheumatology Research Foundation: Health Professional Research Preceptorship. Dr. Kwakkenbos was supported by a CIHR Banting Postdoctoral Fellowship. Ms. Jewett was supported by a CIHR Doctoral Research Award. Dr. Thombs was supported by an Investigator Salary Award from the Arthritis Society

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

Objective To examine the heterogeneity of global transcriptome patterns in systemic sclerosis (SSc) skin in a large sample of patients with SSc and control subjects. Methods Skin biopsy specimens obtained from 61 patients enrolled in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) cohort and 36 unaffected control subjects with a similar demographic background were examined by Illumina HumanHT-12 bead arrays. Followup experiments using quantitative polymerase chain reaction and immunohistochemical analysis were also performed. Results We identified 2,754 differentially expressed transcripts in SSc patients compared with controls. Clustering analysis revealed 2 prominent transcriptomes in SSc patients: the keratin and fibroinflammatory signatures. Higher keratin transcript scores were associated with shorter disease duration and interstitial lung disease, while higher fibroinflammatory scores were associated with diffuse cutaneous involvement, a higher skin score at the biopsy site, and a higher modified Rodnan skin thickness score. A subgroup of patients with significantly longer disease duration had a normal-like transcript pattern. Analysis of cell type–specific signature scores revealed remarkable heterogeneity across patients. Significantly higher scores were calculated for fibroblasts (72% of patients), microvascular cells (61%), macrophages (54%), and dendritic cells (DCs) (49%). The majority of samples with significantly higher fibroblast scores (35 of 44 [80%]) had significantly increased macrophage and/or DC scores. Further analysis and immunohistochemical staining indicated that the keratin signature was not a general marker of keratinocyte activation but was in fact associated with an activation pattern in hair and adnexal structures. Conclusion Prominent fibroinflammatory and keratin signatures are present in SSc skin. Expression profiles of SSc skin show significant heterogeneity, and this finding might be useful for stratifying patients for targeted therapies or predicting the response to immunosuppression.

Black males have historically experienced life on the margins of society, particularly with regard to their being underserved in their educational experience. Many Black males are drawn to sports as an avenue to social, political, and economic mobility. However, Black males do not often experience the same benefits from sports participation as do other groups such as White males, particularly with regard to educational success. This is particularly true of student athletes who compete at a high level. Given the importance of college readiness and success, this is a concern worth exploring further. This paper describes the experiences of three Black male student athletes who successfully manage their academics and athletics while in high school. Several themes deemed critical to this process are noted.

As the world becomes increasingly interconnected, counselors must learn how to work across, through, and beyond cultural and continental differences (McFadden & Moore, 2002). McFadden (1999) suggested that 'confusion and shifts in political, social, and economic problems that have never been greater than at this time present themselves in every aspect of our lives' (p. xviii). It is reasonable to believe that individuals throughout the world are likely to need assistance from professionals such as mental health counselors. The general consensus among counseling professionals who are consistently being exposed to diverse cultures is that there is a need to learn how to create a caring counseling environment that 'transcends cultural, ethnic, racial, and national boundaries' (McFadden, 1999, p. xvi).

Systemic Sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and internal organs, as well as vasculopathy and immune dysregulation. SSc is a clinically heterogeneous disease and presents with 3 distinct subphenotypes, limited, diffuse and “sine” based on the severity of skin involvement. This classification also reflects internal organ involvement which can range from minimal to rapidly progressive disease resulting in premature death. Finally, SSc is characterized by the production of mutually exclusive antinuclear antibodies (ANA) subtypes that are associated with different clinical manifestations, disease phenotypes and prognosis. SSc is a complex disease that entails abnormalities in several different pathways. Its pathogenesis is not well understood but several studies have established that SSc occurs in a genetically susceptible host presumably after encountering environmental exposures or other external triggers.1-3 Genetic studies performed so far reveal that multiple genetic loci contribute to disease susceptibility in SSc.4 The purpose of this review is to discuss the current knowledge of SSc genetics by exploring the observational evidence, the different genetic studies performed to date as well as the most relevant genes discovered by these. We will also explore the concept of gene expression variation and the recently discovered field of epigenetics.

Objective To examine the demographic and clinical characteristics of systemic sclerosis (SSc) patients without antinuclear antibodies (ANA) compared to ANA-positive patients. Methods SSc patients enrolled in the Scleroderma Family Registry and DNA Repository were included. Relevant demographic and clinical data were entered by participating sites or obtained by chart review. ANA and SSc-related antibodies were determined in all investigated patients using commercially available kits at our laboratories. Results This study included 3249 patients, of whom 208 (6.4%) were ANA negative. The proportion of male patients was higher in the ANA-negative group (OR = 1.65; p = 0.008). ANA-negative patients experienced less vasculopathic manifestations of SSc. The percent predicted diffusing capacity of carbon monoxide (DLCO) was higher in ANA-negative patients ( p = 0.03). Pulmonary arterial hypertension (PAH) per right heart catheterization was less common in the ANA-negative group (OR = 0.28; p = 0.03). Furthermore, patients with negative ANA had a lower prevalence of telangiectasias and digital ulcers/pits (OR = 0.59, p = 0.03 and OR=0.38, p = 0.01, respectively). Although diffuse cutaneous involvement was more common, the modified Rodnan Skin Score (mRSS) was lower in the ANA-negative group (2.4 points lower, p = 0.05). Furthermore, they experienced more malabsorption ( p = 0.05). There was no difference in the frequency of pulmonary fibrosis or scleroderma renal crisis. All-cause mortality was not different between the 2 groups ( p = 0.28). Conclusions In conclusion, the results of this study suggest that SSc patients who are ANA negative constitute a distinct subset of SSc with less vasculopathy (less PAH, digital ulcers, and fewer telangiectasias), a greater proportion of males, and possibly, more frequent lower gastrointestinal involvement.

Contains fulltext : 197554.pdf (Publisher’s version ) (Closed access) Objective: Fear of negative evaluation is a common concern among individuals with visible differences but has received limited attention in systemic sclerosis (SSc), which can involve substantial changes to appearance. The Brief Fear of Negative Evaluation Scale (BFNE) was specifically designed to evaluate fear of negative evaluation. There are currently 3 versions of the BFNE with strong demonstrated measurement properties: two 8-item versions (BFNE-S, BFNE-8) and one 12-item version (BFNE-II). The present study evaluated these versions in SSc, and identified the most appropriate version for use among SSc patients. Methods: Participants were 1,010 patients with SSc enrolled in the Scleroderma Patient-Centered Intervention Network cohort. Multiple group confirmatory factor analysis, Cronbach's alpha, and Pearson's product-moment correlations were used to evaluate structural validity, internal consistency reliability, and convergent and divergent validity, respectively. Results: Confirmatory factor analysis demonstrated that 1-factor models fit acceptably well for the 12-item BFNE-II, the 8-item BFNE-S, and the 8-item BFNE-8. Additionally, all Cronbach's alphas demonstrated excellent internal consistency reliability (BFNE-II = 0.98, BFNE-S = 0.97, BFNE-8 = 0.96), and all versions had comparable associations with measures of social anxiety, body-related attitudes, depression, age, and education. Conclusion: Psychometric support was found for all 3 versions of the BFNE, although the longer 12-item BFNE-II did not improve measurement compared to the shorter 8-item versions (BFNE-S and BFNE-8). Of these 2, the BFNE-S has been more widely studied, with strong validity data in a greater number of populations. Therefore, the BFNE-S is recommended to assess fear of negative evaluation among patients with SSc. 7 p.

This study explores the lived experience of two African American women working at predominately white institutions of higher education. A review of the literature suggests research that examines the experiences of African American women in academe is limited. Using an autoethnographic approach, we explore our experiences and how we navigate our roles. Findings suggest that when the appropriate mentoring is in place African American women have a more positive experience navigating the promotion and tenure process.

Background Anabasum (JBT-101) is a synthetic, oral, non-immunosuppressive, preferential CB2 agonist. It inhibits onset and activates resolution of innate immune responses in animal models of systemic sclerosis (SSc). Objectives Evaluate safety and efficacy of anabasum in SSc Methods A double-blind, randomized, placebo (PBO)-controlled Phase 2 trial dosed 42 diffuse cutaneous SSc subjects with disease duration ≤6 years on stable medication including immunosuppressive drugs. Subjects received anabasum 5 mg QD, 20 mg QD, or 20 mg BID on Days 1–28, then 20 mg BID on Days 29–84, or PBO on Days 1–84. Subjects were followed off study drug on Days 85–113. The primary safety outcome was treatment-emergent adverse events (TEAEs). The primary efficacy outcome was improvement in ACR Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) score, combined anabasum group vs PBO, Days 29–113 (end of Weeks 4–16). The five domains of the ACR CRISS are the modified Rodnan skin score, HAQ-DI, patient and physician global assessments, and FVC % predicted. Results Of 42 dosed subjects, 27 (64%) received anabasum and 15 (36%) received PBO. Three anabasum subjects withdrew: 1 (3.7%) for a TEAE of moderate dizziness; 1 withdrew consent; and 1 by physician decision. One PBO subject withdrew consent. Baseline demographic and CRISS domain scores were similar except slightly more anabasum subjects used background immunosuppressive drugs (93% versus 80%, anabasum vs PBO). Seventeen (63%) anabasum subjects had 66 TEAEs, and 9 (60%) PBO subjects had 35 TEAEs. There were no serious, severe, or unexpected TEAEs related to anabasum. Severity and relationship of TEAEs to study drug were similar in both groups. The most frequent TEAEs by MedDRA system (% anabasum vs % PBO) were: nervous system (37% vs 27%); general disorders (30% vs 7%); gastrointestinal (22% vs 20%); infections (22% vs 20%); musculoskeletal (22% vs 13%); and investigations (0% vs 20%). The most frequent TEAEs in anabasum subjects were dizziness (22%) and fatigue (19%) which were usually mild. Anabasum subjects had greater improvement in ACR CRISS scores than PBO subjects (mixed model repeated measures analysis, p=0.044, 1-sided). The median ACR CRISS scores at the end of Weeks 4, 8, 12, and 16 (anabasum vs PBO) were 3.0% vs 1.0%, 19.0% vs 1.0%, 27.5% vs 1.0%, and 33.0% vs 1.0%, respectively. Among anabasum subjects, ∼50% had ACR CRISS ≥20% after 8 weeks of dosing. The individual domains of the ACR CRISS score showed greater improvement, improvement that reached minimal important differences in several domains, and less worsening in anabasum vs PBO groups. Anabasum subjects had greater improvement in SSc skin symptoms and itch. Plasma metabolipidomic profiles showed anabasum, not PBO, shifted lipid mediator production to increase pro-resolving vs pro-inflammatory lipid mediators. Conclusions Anabasum provided significant and medically meaningful efficacy in SSc as assessed by the ACR CRISS score and its individual domains and had acceptable safety and tolerability in this Phase 2 trial. These data support continued clinical development of anabasum for the treatment of SSc. Disclosure of Interest R. Spiera: None declared, L. Hummers: None declared, L. Chung: None declared, T. Frech: None declared, R. Domsic: None declared, D. Furst: None declared, J. Gordon: None declared, M. Mayes: None declared, R. Simms: None declared, S. Constantine Employee of: Corbus Pharmaceuticals, Inc., B. White Employee of: Corbus Pharmaceuticals, Inc.

Background Pneumoproteins are attractive biomarker candidates in systemic sclerosis (SSc) related interstitial lung disease (ILD) because they are easily obtainable and lung-specific. KL-6 and CCL-18 (PARC) have been previously reported as promising predictive biomarkers of lung parenchymal damage in multiple disorders including SSc-ILD. Objectives Our goal was to determine the predictive significance of these two pneumoproteins for forced vital capacity % (FVC) decline within the first year of follow-up in patients with early SSc-ILD, in order to inform individualized care in routine clinical practice and facilitate enrichment strategies in clinical trials. Methods GENISOS (Genetics versus ENvironment In Scleroderma Outcome Study) cohort patients who had ILD verified by imaging and available pulmonary function tests at enrollment plus 12–18 months thereafter, were included in this study. All patients had disease duration ≤5 years at enrollment. FVC, expressed as percentage of predicted value was used as surrogate for severity of ILD. Annualized percent change in FVC at one year follow up was calculated. Baseline demographic, clinical variables and two pneumo-proteins, KL-6 and CCL-18 were investigated. KL-6 and CCL-18 were measured in the plasma by commercially available, validated ELISA kits. Linear regression with baseline clinical and demographic variables as independent variables was performed in univariable and multivariable models. Only variables that reached p Results A total of 82 patients with early SSc-ILD were included, 18 were male and 45 had diffuse cutaneous involvement. Mean disease duration was 2.3 years. Rate of FVC% predicted change over time ranged from -0.23 to 0.38, indicating a highly variable course. Baseline KL-6 levels were higher in patients than healthy controls (p p =0.04). Upon categorizing KL-6 using a previously determined optimal cut-off of 1273 u/mL (1), its predictive significance remained in the univariate (p=0.01) and multivariable analyses adjusted for Scl-70, disease type and gender (b=-0.03, p =0.04). Twenty nine (34.5%) patients had KL6 levels equal or above 1273 u/mL. Although CCL-18 was higher in patients than controls ( Conclusions KL-6 but not CCl-18 is predictive of early SSc-ILD progression. In this study, we also validated the previously proposed cut-off of 1273 for KL-6 in an independent cohort. KL-6 is a promising pneumoprotein that can inform individualized clinical care and contribute to enrichment strategies in clinical trials of SSc-ILD. References Kuwana M, Shirai Y, Takeuchi T. Elevated Serum Krebs von den Lungen-6 in Early Disease Predicts Subsequent Deterioration of Pulmonary Function in Patients with Systemic Sclerosis and Interstitial Lung Disease. J Rheumatol 2016. Acknowledgements This study was funded by the National Institute of Health NIH/NIAMS K23 AR061436 (Assassi); NIH/NIAMS P50-AR05414 and the Department of Defense Congressionally Directed Medical Research Programs (W81XWH-07–01–0111- Mayes). Disclosure of Interest None declared

Objective.To examine the clinical correlates and survival in patients with antifibrillarin antibodies (AFA) in a large international study population consisting of well-characterized systemic sclerosis (SSc) cohorts from Canada, Australia, and the United States.Methods.Baseline clinical data from the prospective cohorts (Canadian Scleroderma Research Group, the Australian Scleroderma Cohort Study, and the American Genetics versus Environment in Scleroderma Outcome Study) were investigated. Clinical variables were harmonized and sera were tested for AFA using a commercially available SSc profile line immunoassay, regardless of the immunofluorescence staining pattern. Association of demographic and clinical features with AFA was investigated by logistic or linear regression. Further, a survival analysis was performed by Cox regression analysis.Results.A total of 1506 patients with SSc with complete serological profiles were included in the study. Fifty-two patients (3.5%) had antibodies detected against fibrillarin. Patients of African descent and Native North American ethnicity were more likely to be AFA-positive compared with other ethnicities. After adjustment for demographic factors, diffuse involvement, and intestinal bacterial overgrowth requiring antibiotics, gastrointestinal reflux disease showed a trend for association with AFA. Further, AFA positivity was associated with shorter survival independently of demographic factors and disease type (HR 1.76, 95% CI 1.11–2.79, p = 0.016).Conclusion.In this large multinational SSc cohort, AFA was associated with Native American ethnicity and was an independent predictor of mortality.

The modified Rodnan skin score (mRSS) is a measure of skin thickness and is used as a primary or secondary outcome measure in clinical trials of systemic sclerosis (scleroderma). This state-of-art review provides a historical perspective of the development of the mRSS, summarizes the performance of mRSS as an outcome measure, provides guidance on assessing mRSS, and makes recommendations for incorporation of the mRSS into clinical trials.

Objective Skin and musculoskeletal involvement are frequently present early in diffuse cutaneous systemic sclerosis (dcSSc). The current study examined the correlates for skin and musculoskeletal measures in a 1-year longitudinal observational study.

Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10-49; OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3(P-valuesEU = 10-27-10-32, OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credibleset of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3. © The Author 2014.

Objective Systemic sclerosis (SSc) is a chronic autoimmune disease clinically manifesting as progressive fibrosis of the skin and internal organs. Recent microarray studies demonstrated that cadherin 11 (Cad-11) expression is increased in the affected skin of patients with SSc. The purpose of this study was to examine our hypothesis that Cad-11 is a mediator of dermal fibrosis. Methods Biopsy samples of skin from SSc patients and healthy control subjects were used for real-time quantitative polymerase chain reaction analysis to assess Cad-11 expression and for immunohistochemistry to determine the expression pattern of Cad-11. To determine whether Cad-11 is a mediator of dermal fibrosis, Cad-11–deficient mice and anti–Cad-11 monoclonal antibodies (mAb) were used in the bleomycin-induced dermal fibrosis model. In vitro studies with dermal fibroblasts and bone marrow–derived macrophages were used to determine the mechanisms by which Cad-11 contributes to the development of tissue fibrosis. Results Levels of messenger RNA for Cad-11 were increased in skin biopsy samples from patients with SSc and correlated with the modified Rodnan skin thickness scores. Cad-11 expression was localized to dermal fibroblasts and macrophages in SSc skin. Cad-11–knockout mice injected with bleomycin had markedly attenuated dermal fibrosis, as quantified by measurements of skin thickness, collagen levels, myofibroblast accumulation, and profibrotic gene expression, in lesional skin as compared to the skin of wild-type mice. In addition, anti–Cad-11 mAb decreased fibrosis at various time points in the bleomycin-induced dermal fibrosis model. In vitro studies demonstrated that Cad-11 regulated the production of transforming growth factor β (TGFβ) by macrophages and the migration of fibroblasts. Conclusion These data demonstrate that Cad-11 is a mediator of dermal fibrosis and TGFβ production and suggest that Cad-11 may be a therapeutic target in SSc.

Objective Despite being a common problem in systemic sclerosis (SSc; scleroderma), the extant literature on pain has primarily focused on biomedical correlates, or bivariate relationships with a few psychological characteristics. There is a need to investigate the more heuristic biopsychosocial model, which incorporates the simultaneous contributions of medical, psychological, and social variables in understanding pain. Methods Patients with SSc (n = 333) received clinical examinations and completed self-report surveys at enrollment in the Genetics versus Environment in Scleroderma Outcome Study. Latent profile analysis was used to derive biopsychosocial profiles of patients using skin thickening, percent predicted forced vital lung capacity, perceived physical health, health worry, mental health, and social support. The profiles were examined in relation to pain and pain medication usage. Results A 3-profile solution provided the best fit to the data. Based on the biopsychosocial indicators, the profiles were characterized as managing (n = 217), resilient (n = 86), and distressed (n = 30). Between-group differences for pain emerged, with the distressed group, whose disease was less severe than the resilient group, reporting the highest pain and the greatest utilization of pain medication. Conclusion Clinicians should consider biopsychosocial characteristics as contributing factors to the experience of pain in patients with SSc. Patients who are similar to those in the distressed profile may be at an increased risk for pain and would likely benefit from a referral to a behavioral health or other ancillary service provider for pain management, rather than relying solely on pharmacologic therapies.

Vasoconstriction accompanied by changes in skin color is a normal physiologic response to cold. The distinction between this normal physiology and Raynaud’s phenomenon (RP) has yet to be well characterized. In anticipation of the 9th International Congress on Autoimmunity, a panel of 12 RP experts from 9 different institutes and four different countries were assembled for a Delphi exercise to establish new diagnostic criteria for RP. Relevant investigators with highly cited manuscripts in Raynaud’s-related research were identified using the Web of Science and invited to participate. Surveys at each stage were administered to participants via the on-line SurveyMonkey software tool. The participants evaluated the level of appropriateness of statements using a scale of 1 (extremely inappropriate) through 9 (extremely appropriate). In the second stage, panel participants were asked to rank rewritten items from the first round that were scored as “uncertain” for the diagnosis of RP, items with significant disagreement (Disagreement Index > 1), and new items suggested by the panel. Results were analyzed using the Interpercentile Range Adjusted for Symmetry (IPRAS) method. A 3-Step Approach to diagnose RP was then developed using items the panelists “agreed” were “appropriate” diagnostic criteria. In the final stage, the panel was presented with the newly developed diagnostic criteria and asked to rate them against previous models. Following the first two iterations of the Delphi exercise, the panel of 12 experts agreed that 36 of the items were “appropriate,” 12 items had “uncertain” appropriateness, and 13 items were “inappropriate” to use in the diagnostic criteria of RP. Using an expert committee, we developed a 3-Step Approach for the diagnosis of RP and 5 additional criteria for the diagnosis of primary RP. The committee came to an agreement that the proposed criteria were “appropriate and accurate” for use by physicians to diagnose patients with RP.

Contains fulltext : 137489.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Classification criteria for systemic sclerosis (SSc) are being developed. The objectives were to develop an instrument for collating case data and evaluate its sensibility; use forced-choice methods to reduce and weight criteria; and explore agreement among experts on the probability that cases were classified as SSc. STUDY DESIGN AND SETTING: A standardized instrument was tested for sensibility. The instrument was applied to 20 cases covering a range of probabilities that each had SSc. Experts rank ordered cases from highest to lowest probability; reduced and weighted the criteria using forced-choice methods; and reranked the cases. Consistency in rankings was evaluated using intraclass correlation coefficients (ICCs). RESULTS: Experts endorsed clarity (83%), comprehensibility (100%), face and content validity (100%). Criteria were weighted (points): finger skin thickening (14-22), fingertip lesions (9-21), friction rubs (21), finger flexion contractures (16), pulmonary fibrosis (14), SSc-related antibodies (15), Raynaud phenomenon (13), calcinosis (12), pulmonary hypertension (11), renal crisis (11), telangiectasia (10), abnormal nailfold capillaries (10), esophageal dilation (7), and puffy fingers (5). The ICC across experts was 0.73 [95% confidence interval (CI): 0.58, 0.86] and improved to 0.80 (95% CI: 0.68, 0.90). CONCLUSIONS: Using a sensible instrument and forced-choice methods, the number of criteria were reduced by 39% (range, 23-14) and weighted. Our methods reflect the rigors of measurement science and serve as a template for developing classification criteria.

BackgroundIncreased circulatory levels of the chemokine CXCL4 have been associated with the presence of interstitial lung disease (ILD) in an observational study of patients with systemic sclerosis (SSc). The purpose of the present study was to evaluate the relationship between baseline CXCL4 level and extent of ILD in the context of a randomized controlled trial and to determine whether changes in CXCL4 levels in response to immunosuppression are associated with future progression of SSc-ILD.MethodsA total of 142 SSc-ILD patients from Scleroderma Lung Study (SLS) II were randomized in a double-blind, parallel-arm trial, to receive mycophenolate (MMF) for 2years or oral cyclophosphamide (CYC) for 1year followed by 1year of placebo. Plasma CXCL4 levels were measured at baseline, 12months, and 24months in SLS II participants (N = 136) and at a single time point in healthy controls (N = 67). A mixed-effects model evaluated the relationship between change in CXCL4 levels and SSc-ILD progression. The primary outcome was the course of the forced vital capacity.ResultsBaseline CXCL4 levels were significantly higher in SSc-ILD patients compared with healthy controls (2699 ± 1489ng/ml vs 2233 ± 1351ng/ml (mean ± SD); P = 0.019). However, no significant correlations were identified between CXCL4 levels and extent of ILD at baseline, as measured by the forced vital capacity, diffusing capacity of carbon monoxide, or radiographic extent of ILD. Plasma CXCL4 decreased significantly from baseline to 12months in all patients (CYC: P

The objectives of this study were to develop a standard classification of digital ulcers (DUs) in systemic sclerosis (SSc) for use in observational or therapeutic studies and to assess the reliability of these definitions as well as of the measurement of ulcer area. Ten North American rheumatologists with expertise in SSc reviewed multiple photos of DUs, examined four SSc subjects with DUs, and came to a consensus on the definitions for digital, active, healed, and indeterminate ulcers. These ten raters then examined the right hand of ten SSc subjects twice and the left hand once to classify ulcers and to measure ulcer area. Weighted and Fleiss kappa were used to calculate intra- and interrater agreement on classification of ulcers, and intraclass correlation coefficient (ICC) was used to assess agreement on ulcer area. Because the traditional ICC calculations relied on a small number of ulcers, ICCs were recalculated using the results of linear mixed models to evaluate the variance components of observations on all the data. Intrarater kappa for classifying DU as not an ulcer/healed ulcer versus active/indeterminate ulcer was substantial (0.76), and interrater kappa was moderate (0.53). The ICC for ulcer area using the linear mixed models was moderate both for intrarater (0.57) and interrater (0.48) measurements. A consensus for the classification of DUs in SSc was developed, and after a training session, rheumatologists with expertise in SSc are able to reliably classify DUs and to measure ulcer area.

Systemic sclerosis (SSc) is characterized by the triad of vasculopathy, immune dysregulation, and fibrosis and is associated with high morbidity and mortality. Interstitial lung disease (ILD) is the primary cause of SSc-related mortality (1,2), and the available treatment options for this disease manifestation have limited efficacy (3,4). Furthermore, the course of lung involvement in SSc is highly variable. Even though deterioration of pulmonary function is slowly progressive in many SSc patients, ~15% have a rapidly progressive course (5). Clinicians are currently unable to predict reliably early in the course of disease which patients will develop significant ILD. Therefore, the treatment of SSc-related ILD is delayed until fibrosis has clearly occurred in the pulmonary tissue. Gene expression profiling of affected end organs has provided a valuable resource for development of biomarkers in the field of oncology. Although the lung is a prominently affected end organ in SSc, its inaccessibility has precluded the widespread use of pulmonary tissue for research and clinical purposes. The global gene expression profile of SSc pulmonary tissue has only been studied in patients with end-stage disease undergoing lung transplantation (6). Skin is another prominently affected and easily accessible organ in patients with SSc. Global gene expression studies of the skin tissue of patients with SSc have demonstrated a distinct gene expression profile compared to controls; an inflammatory activation pattern and a fibrotic signature were seen (7,8). In a larger study with 24 SSc patients, patients with diffuse cutaneous SSc (dcSSc) could be subdivided into 3 distinct groups and patients with limited cutaneous SSc (lcSSc) into 2 groups based on skin gene expression profiling. A subgroup of patients with lcSSc and dcSSc showed a pattern of inflammatory genes that included interferon-inducible genes (9) and interleukin-13 (IL-13)–inducible genes (10). Another subgroup of SSc patients with diffuse skin involvement showed a fibrotic gene expression profile containing transforming growth factor β (TGFβ)–responsive genes (11). In that study, none of the patients with dcSSc in the subgroup without activation of TGFβ response genes had ILD (defined as a dichotomous outcome based on high-resolution computed tomography [HRCT] results). There are no published reports of skin transcript correlates of severity of ILD in patients with SSc. In the present study, we investigated the skin transcript correlates of ILD severity in a large group of patients with SSc. Considering that skin tissue can be obtained during routine clinical practice, the results of the present hypothesis-generating study can provide valuable information for identification of novel biomarkers and therapeutic targets.

OBJECTIVE: The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. METHODS: Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc. RESULTS: It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. CONCLUSION: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

Objective There are no identified clinical markers that reliably predict long-term progression of interstitial lung disease (ILD) in systemic sclerosis (SSc; scleroderma). Elevated C-reactive protein (CRP) levels have been reported in SSc patients. We examined the predictive significance of CRP level for long-term ILD progression in a large early SSc cohort.

Objective.To examine the predictive significance of 2 pneumoproteins, surfactant protein D (SP-D) and CC-chemokine ligand 18 (CCL18), for the course of systemic sclerosis (SSc)-related interstitial lung disease.Methods.The pneumoproteins were determined in the baseline plasma samples of 266 patients with early SSc enrolled in the GENISOS observational cohort. They also were measured in 83 followup patient samples. Pulmonary function tests were obtained annually. The primary outcome was decline in forced vital capacity (FVC percentage predicted) over time. The predictive significance for longterm change in FVC was investigated by a joint analysis of longitudinal measurements (sequentially obtained FVC percentage predicted) and survival data.Results.SP-D and CCL18 levels were both higher in patients with SSc than in matched controls (p < 0.001 and p = 0.015, respectively). Baseline SP-D levels correlated with lower concomitantly obtained FVC (r = −0.27, p < 0.001), but did not predict the short-term decline in FVC at 1 year followup visit or its longterm decline rate. CCL18 showed a significant correlation with steeper short-term decline in FVC (p = 0.049), but was not a predictor of its longterm decline rate. Similarly, a composite score of SP-D and CCL18 was a significant predictor of short-term decline in FVC but did not predict its longterm decline rate. Further, the longitudinal change in these 2 pneumoproteins did not correlate with the concomitant percentage change in FVC.Conclusion.SP-D correlated with concomitantly obtained FVC, while CCL18 was a predictor of short-term decline in FVC. However, neither SP-D nor CCL18 was a longterm predictor of FVC course in patients with early SSc.

ObjectiveTo evaluate whether the systemic sclerosis (SSc)-associated IRAK1 non-synonymous single-nucleotide polymorphism rs1059702 is responsible for the Xq28 association with SSc or whether there are other independent signals in the nearby methyl-CpG-binding protein 2 gene (MECP2).MethodsWe analysed a total of 3065 women with SSc and 2630 unaffected controls from five independent Caucasian cohorts. Four tag single-nucleotide polymorphisms of MECP2 (rs3027935, rs17435, rs5987201 and rs5945175) and the IRAK1 variant rs1059702 were genotyped using TaqMan predesigned assays. A meta-analysis including all cohorts was performed to test the overall effect of these Xq28 polymorphisms on SSc.ResultsIRAK1 rs1059702 and MECP2 rs17435 were associated specifically with diffuse cutaneous SSc (PFDR=4.12×10−3, OR=1.27, 95% CI 1.09 to 1.47, and PFDR=5.26×10−4, OR=1.30, 95% CI 1.14 to 1.48, respectively), but conditional logistic regression analysis showed that the association of IRAK1 rs1059702 with this subtype was explained by that of MECP2 rs17435. On the other hand, IRAK1 rs1059702 was consistently associated with presence of pulmonary fibrosis (PF), because statistical significance was observed when comparing SSc patients PF+ versus controls (PFDR=0.039, OR=1.30, 95% CI 1.07 to 1.58) and SSc patients PF+ versus SSc patients PF− (p=0.025, OR=1.26, 95% CI 1.03 to 1.55).ConclusionsOur data clearly suggest the existence of two independent signals within the Xq28 region, one located in IRAK1 related to PF and another in MECP2 related to diffuse cutaneous SSc, indicating that both genes may have an impact on the clinical outcome of the disease.

Unusual fears have long been recognized as common in autism, but little research exists. In our sample of 1033 children with autism, unusual fears were reported by parents of 421 (41%) of the children, representing 92 different fears. Many additional children had common childhood fears (e.g., dogs, bugs, and the dark). More than half of children with unusual fears had fears of mechanical things, heights, and/or weather. The most common unusual fear was fear of toilets, and the most common category was fear of mechanical things. Amazingly, many of the fears reported in our sample were described in children with autism 70 years ago by Kanner, including fear of vacuum cleaners, elevators, mechanical toys, swings, and the wind. Children with autism perceive, experience, and react to the world differently than children without autism. What is tolerable for most children (e.g., clouds in the sky, a change in activity or routine, sensory input, or a performance request) might be terrifying, distressing, or infuriating for a child with autism. It is critical to assess for unusual and common fears in children with autism because they are present in the majority of these children, they further impair functioning, and effective treatment is available.

In spite of research suggesting the importance of diverse professionals in education (Mattison & Aber, 2007), no studies have explored the professional experiences of school counselors of Color. In...

In this article, the authors describe the unique and complex challenges that educators face when working in low-performing schools in impoverished communities. Further, the authors examine the impact these challenges may have on the academic achievement and special education placement of African American students. The authors also discuss how educational outcomes can be improved for African American learners through collaborative efforts among stakeholders, the use of empirically validated academic and social behavior strategies, and culturally responsive instruction.

Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by excessive collagen deposition in the skin and internal organs with associated vasculopathy and autoantibody production. Clinically SSc is divided into two main groups: limited and diffuse cutaneous disease. The limited form is characterized by skin thickening that is confined to areas distal to the elbows and knees and generally is associated with less severe internal organ involvement. The diffuse form involves skin thickening proximal to the elbows and the knees as well as distal areas and is associated with more severe organ damage. This chapter will focus on the epidemiology of SSc including both limited and diffuse cutaneous forms along with environmental and infectious risk factors.

Objective There are few clinical predictors of the progression of systemic sclerosis (SSc)-related interstitial lung disease (ILD). The purpose of this study was to examine the predictive significance of key cytokines for long-term progression of ILD and survival in 2 independent cohorts of patients with early SSc. Methods Plasma levels of 11 Th1/Th2 cytokines (interleukin-1β [IL-1β], IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, tumor necrosis factor, CCL2, interferon-inducible T cell α chemoattractant, and interferon-γ-inducible 10-kd protein) were measured in 266 patients with early SSc in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) discovery cohort. Levels of CCL2, IL-10, and IL-6 were measured in 171 patients with early SSc in the Canadian Scleroderma Research Group (CSRG) replication cohort. The primary outcome measure was a decline in the forced vital capacity percent predicted (FVC%) value over time. A joint analysis of longitudinal FVC% values and survival was performed. Results After adjustment for age, sex, and ethnicity, CCL2 and IL-10 were found to be significant predictors of ILD progression in the discovery cohort. Higher CCL2 levels predicted a faster decline in FVC% values (b = -0.57, P = 0.032), while higher IL-10 levels predicted a slower decline (b = 0.26, P = 0.01). A higher CCL2 value was also predictive of poorer survival (hazard ratio 1.76, P = 0.030). In the CSRG replication cohort, higher CCL2 levels predicted a faster decline in FVC% values (b = -0.58, P = 0.038), but neither IL-10 nor IL-6 had predictive significance. A higher CCL2 level also predicted poorer survival (hazard ratio 3.89, P = 0.037). Conclusion Higher CCL2 levels in the circulation were predictive of ILD progression and poorer survival in patients with early SSc, findings that support the notion that CCL2 has a role as a biomarker and potential therapeutic target.

Pain is a common but understudied quality of life concern in systemic sclerosis (SSc). This investigation sought to describe patient-reported pain during the early phase of the disease and to examine potential predictors of this over time. A prospective cohort (N = 316) of patients with early-disease SSc from the Genetics versus ENvironment In Scleroderma Outcome Study (GENISOS) were followed for 3 years. Multilevel modeling was used to describe longitudinal changes in pain and the extent to which pain variance was explained by disease type, emotional health, perceived physical health, health worry, and social support. Patient-reported pain remained relatively stable, with slight improvement over time. More severe disease type was associated with worse initial pain, but the association was reduced to nonsignificance after accounting for the psychosocial variables. Better emotional health and perceived physical health were associated with lower initial pain. There were marginal interactive effects for perceived physical health and social support such that initial perceptions of poorer physical health, and higher social support, were predictive of greater improvements in pain over time. These data suggest that emotional health, perceived physical health, and social support are more relevant to longitudinal SSc pain than disease severity and that perceived physical health and social support may impact pain trajectories. Researchers and rheumatology health professionals should consider these factors in comprehensive pain models and pain management protocols.

There has been a substantial increase in research concerning the identification and support of twice exceptional students. However, much of the scientific and theoretical literature exclude the experiences and perspectives of twice exceptional African American students. This chapter focuses specifically on the experiences and needs of twice exceptional African American students, including those challenges around identification and navigating the school environment. In this chapter, the authors also discuss how school counselors may use a group counseling intervention to help twice exceptional African American students achieve healthy identities (i.e., race, giftedness, disability) needed to achieve their educational goals.

Item does not contain fulltext Body concealment is an important component of appearance distress for individuals with disfiguring conditions, including scleroderma. The objective was to replicate the validation study of the Body Concealment Scale for Scleroderma (BCSS) among 897 scleroderma patients. The factor structure of the BCSS was evaluated using confirmatory factor analysis and the Multiple-Indicator Multiple-Cause model examined differential item functioning of SWAP items for sex and age. Internal consistency reliability was assessed via Cronbach's alpha. Construct validity was assessed by comparing the BCSS with a measure of body image distress and measures of mental health and pain intensity. Results replicated the original validation study, where a bifactor model provided the best fit. The BCSS demonstrated strong internal consistency reliability and construct validity. Findings further support the BCSS as a valid measure of body concealment in scleroderma and provide new evidence that scores can be compared and combined across sexes and ages. 8 p.

Summary Background 12 months of oral cyclophosphamide has been shown to alter the progression of scleroderma-related interstitial lung disease when compared with placebo. However, toxicity was a concern and without continued treatment the efficacy disappeared by 24 months. We hypothesised that a 2 year course of mycophenolate mofetil would be safer, better tolerated, and produce longer lasting improvements than cyclophosphamide. Methods This randomised, double-blind, parallel group trial enrolled patients from 14 US medical centres with scleroderma-related interstitial lung disease meeting defined dyspnoea, pulmonary function, and high-resolution CT (HRCT) criteria. The data coordinating centre at the University of California, Los Angeles (UCLA, CA, USA), randomly assigned patients using a double-blind, double-dummy, centre-blocked design to receive either mycophenolate mofetil (target dose 1500 mg twice daily) for 24 months or oral cyclophosphamide (target dose 2·0 mg/kg per day) for 12 months followed by placebo for 12 months. Drugs were given in matching 250 mg gel capsules. The primary endpoint, change in forced vital capacity as a percentage of the predicted normal value (FVC %) over the course of 24 months, was assessed in a modified intention-to-treat analysis using an inferential joint model combining a mixed-effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data. The study was registered with ClinicalTrials.gov, number NCT00883129. Findings Between Sept 28, 2009, and Jan 14, 2013, 142 patients were randomly assigned to either mycophenolate mofetil (n=69) or cyclophosphamide (n=73). 126 patients (mycophenolate mofetil [n=63] and cyclophosphamide [n=63]) with acceptable baseline HRCT studies and at least one outcome measure were included in the primary analysis. The adjusted % predicted FVC improved from baseline to 24 months by 2·19 in the mycophenolate mofetil group (95% CI 0·53–3·84) and 2·88 in the cyclophosphamide group (1·19–4·58). The course of the % FVC did not differ significantly between the two treatment groups based on the prespecified primary analysis using a joint model (p=0·24), indicating that the trial was negative for the primary endpoint. However, in a post-hoc analysis of the primary endpoint, the within-treatment change from baseline to 24 months derived from the joint model showed that the % FVC improved significantly in both the mycophenolate mofetil and cyclophosphamide groups. 16 (11%) patients died (five [7%] mycophenolate mofetil and 11 [15%] cyclophosphamide), with most due to progressive interstitial lung disease. Leucopenia (30 patients vs four patients) and thrombocytopenia (four vs zero) occurred more often in patients given cyclophosphamide than mycophenolate mofetil. Fewer patients on mycophenolate mofetil than on cyclophosphamide prematurely withdrew from study drug (20 vs 32) or met prespecified criteria for treatment failure (zero vs two). The time to stopping treatment was shorter in the cyclophosphamide group (p=0·019). Interpretation Treatment of scleroderma-related interstitial lung disease with mycophenolate mofetil for 2 years or cyclophosphamide for 1 year both resulted in significant improvements in prespecified measures of lung function over the 2 year course of the study. Although mycophenolate mofetil was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than cyclophosphamide was not confirmed. These findings support the potential clinical effectiveness of both cyclophosphamide and mycophenolate mofetil for progressive scleroderma-related interstitial lung disease, and the present preference for mycophenolate mofetil because of its better tolerability and toxicity profile. Funding National Heart, Lung and Blood Institute, National Institutes of Health; with drug supply provided by Hoffmann-La Roche and Genentech.

Appearance concerns are common in systemic sclerosis (SSc) and have been linked to younger age and more severe disease. No study has examined their association with sex or race/ethnicity.SSc patients were sampled from the Scleroderma Patient-centered Intervention Network Cohort. Presence of appearance concerns was assessed with a single item, and medical and sociodemographic information were collected.Of 644 patients, appearance concerns were present in 72%, including 421 of 565 women (75%), 42 of 79 men (53%), 392 of 550 patients who identified as White (71%), 35 of 41 who identified as Black (85%), and 36 of 53 who identified as another race/ethnicity (68%). In multivariate analysis, women had significantly greater odds of reporting appearance concerns than men (odds ratio (OR)=2.97, 95% confidence interval (CI)=1.78-4.95, p.001). Black patients had significantly greater odds of appearance concerns than White patients in unadjusted (OR=2.64, 95% CI=1.01-6.34, p=.030), but not multivariate analysis (OR=1.76, 95% CI=0.67-4.60, p=.250). Compared to a general population sample, appearance concerns were substantially more common in SSc, particularly for men across all age groups and for younger women. The most commonly reported features of concern were related to the face and head, followed by the hands and fingers; this did not differ by sex or race/ethnicity.Appearance concerns were common in SSc. Women were substantially more likely than men to have appearance concerns. Although non-significant in multivariate analysis, Black patients were more likely to have concerns than White patients, likely due to more severe changes in appearance.

ObjectiveEarly diffuse cutaneous systemic sclerosis (dcSSc) is characterized by rapid changes in the skin and internal organs. The objective of this study was to develop a composite response index in dcSSc (CRISS) for use in randomized controlled trials (RCTs).MethodsWe developed 150 paper patient profiles with standardized clinical outcome elements (core set items) using patients with dcSSc. Forty scleroderma experts rated 20 patient profiles each and assessed whether each patient had improved or not improved over a period of 1 year. Using the profiles for which raters had reached a consensus on whether the patients were improved versus not improved (79% of the profiles examined), we fit logistic regression models in which the binary outcome referred to whether the patient was improved or not, and the changes in the core set items from baseline to followup were entered as covariates. We tested the final index in a previously completed RCT.ResultsSixteen of 31 core items were included in the patient profiles after a consensus meeting and review of test characteristics of patient-level data. In the logistic regression model in which the included core set items were change over 1 year in the modified Rodnan skin thickness score, the forced vital capacity, the patient and physician global assessments, and the Health Assessment Questionnaire disability index, sensitivity was 0.982 (95% confidence interval 0.982-0.983) and specificity was 0.931 (95% confidence interval 0.930-0.932), and the model with these 5 items had the highest face validity. Subjects with a significant worsening of renal or cardiopulmonary involvement were classified as not improved, regardless of improvements in other core items. With use of the index, the effect of methotrexate could be differentiated from the effect of placebo in a 1-year RCT (P = 0.02).ConclusionWe have developed a CRISS that is appropriate for use as an outcome assessment in RCTs of early dcSSc.

To examine the range and responsiveness to change of clinical outcome measures and study predictors of clinical response in patients with diffuse cutaneous systemic sclerosis (dcSSc) in the context of clinical trials.Data were combined from 629 patients with dcSSc who participated in 7 multicenter clinical therapeutic trials. Trials used common outcome measures: modified Rodnan skin thickness score (MRSS), Health Assessment Questionnaire disability index (HAQ DI), patient's global assessment of disease activity, pulmonary function tests (forced vital capacity, diffusing capacity for carbon monoxide), hand span, and oral aperture.The combined database included 629 patients (82% women, mean ± SD age 46.5 ± 11.8 years, mean ± SD disease duration 19.4 ± 15.9 months). Outcomes tended to improve during trials for patients with more severe disease at study entry and to worsen for patients with less severe disease at entry. Disease duration was mildly negatively predictive of change in MRSS at 6 months (r = -0.27, P0.001), and substantial bidirectional variation in change in MRSS and HAQ DI score was seen across the spectrum of disease duration. Sixty-three percent of patients with "early" disease (disease duration18 months) had a decline in MRSS, and 37% had an increase in MRSS. Eighty-one percent of patients with "late" disease (disease duration ≥ 18 months) had a decline in MRSS, and 19% had an increase in MRSS. Multivariate mixed models did not demonstrate that any baseline variables were strongly predictive of subsequent outcome.Among patients with dcSSc enrolled in clinical trials, standard outcome measures tend to improve in those with more severe disease at study entry and to worsen in those with less severe disease at entry. Overall, the MRSS improves during trials, while HAQ DI scores and lung function are mostly static. None of these variables, including disease duration, reliably identifies groups of subjects whose MRSS will predictably increase or decrease in the course of a clinical trial. These findings have important implications for clinical trial design in scleroderma.

Objective The first genome-wide association study (GWAS) of systemic sclerosis (SSc) demonstrated three non-major histocompatibility complex (MHC) susceptibility loci. The goal of this study was to investigate the impact of these gene variants on survival and severity of interstitial lung disease (ILD) in SSc. Methods The authors examined 1443 Caucasian SSc patients enrolled in the G enetics versus E nvironment I n S cleroderma O utcome S tudy (GENISOS) and Scleroderma Family Registry (n = 914 – discovery cohort) and The Johns Hopkins Scleroderma Cohort (n = 529 – replication cohort). Forced vital capacity (FVC)% predicted was used as a surrogate for ILD severity. Five single nucleotide polymorphisms, IRF5 (rs10488631, rs12537284, rs4728142), STAT4 (rs3821236), CD247 (rs2056626) reached genome-wide significance in the SSc-GWAS and were examined in the current study. Results Overall, 15.5% of the patients had died over the follow-up period of 5.5 years. The IRF5 rs4728142 minor allele was predictive of longer survival in the discovery cohort (p = 0.021) and in the independent replication cohort (p = 0.047) and combined group (HR: 0.75, 95% CI 0.62 to 0.90, p = 0.002). The association of this SNP with survival was independent of age at disease onset, disease type and autoantibody profile (anticentromere and antitopoisomerase antibodies). The minor allele frequency of IRF5 rs4728142 was 49.4%. Moreover, IRF5 rs4728142 minor allele correlated with higher FVC% predicted at enrolment (p = 0.019). Finally, the IRF5 rs4728142 minor allele was associated with lower IRF5 transcript expression in patients and controls (p = 0.016 and p = 0.034, respectively), suggesting that the IRF5 , rs4728142 SNP, may be functionally relevant. Conclusion An SNP in the IRF5 promoter region (rs4728142), associated with lower IRF5 transcript levels, was predictive of longer survival and milder ILD in patients with SSc.

Children with ADHD and autism have some similar features, complicating a differential diagnosis. The purpose of our study was to determine the degree to which core ADHD and autistic symptoms overlap in and discriminate between children 2–16 years of age with autism and ADHD. Our study demonstrated that 847 children with autism were easily distinguished from 158 children with ADHD. All children with autism had 15 or more of the 30 Checklist for Autism Spectrum Disorder symptoms (mean 22), and none of the children with ADHD did (mean 4). Three of the symptoms were present only in children with autism. Almost all 30 symptoms were found in over half of the children with autism, whereas none were present in the majority of children with ADHD-Inattentive type (ADHD-I) or in children with ADHD-Combined type (ADHD-C) without comorbid oppositional-defiant disorder. In contrast, ADHD symptoms were common in autism. Children with low and high functioning autism and ADHD-C did not differ on maternal ratings of attention deficit, impulsivity, and hyperactivity. For children with normal intelligence, nonsignificant differences were found between children with autism, ADHD-C, and ADHD-I on neuropsychological tests including measures of attention, working memory, processing speed, and graphomotor skills.