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Transforming growth factor β (TGFβ) and platelet-derived growth factor (PDGF) may play a critical role in systemic sclerosis (SSc)-related interstitial lung disease (ILD), and imatinib is a potent inhibitor of TGFβ and PDGF production. In this 1-year, phase I/IIa open-label pilot study of imatinib in patients with SSc-related active ILD, our primary aim was to assess the safety of imatinib; we also explored its efficacy.We recruited 20 SSc patients with a forced vital capacity (FVC) of85% predicted, dyspnea on exertion, and presence of a ground-glass appearance on high-resolution computed tomography. Patients received oral therapy with imatinib (up to 600 mg/day) for a period of 1 year. Adverse events were recorded, pulmonary function was tested, and the modified Rodnan skin thickness score (MRSS) was assessed every 3 months. The course of changes in lung function, the Health Assessment Questionnaire (HAQ) disability index (DI), and the MRSS were modeled over the period of study to explore treatment efficacy.The majority of patients were female (65%), Caucasian (75%), and had diffuse cutaneous SSc (70%). At baseline, the mean ± SD FVC % predicted was 65.2 ± 14.0 and the mean ± SD MRSS was 18.7 ± 10.1. The mean ± SD dosage of imatinib was 445 ± 125 mg/day. Of the 20 SSc patients, 12 completed the study, 7 discontinued because of adverse events (AEs), and 1 patient was lost to followup. Common AEs (≥20%) included fatigue, facial/lower extremity edema, nausea and vomiting, diarrhea, generalized rash, and new-onset proteinuria. Treatment with imatinib showed a trend toward improvement in the FVC % predicted (1.74%; P not significant) and the MRSS (3.9 units; P0.001).Use of high-dose daily therapy with imatinib (600 mg/day) in SSc patients with ILD was associated with a large number of AEs. Our experience with AEs suggests that dosages of imatinib lower than 600 mg/day may be appropriate and that further dose ranging analysis is needed in order to understand the therapeutic index of imatinib in SSc.

ObjectiveLumbar spinal stenosis is one of the most commonly diagnosed spinal disorders in older adults. Although the pathophysiology of the clinical syndrome is not well understood, a narrow central canal or intervertebral foramen is an essential or defining feature. The aim of the present study was to estimate the magnitude of genetic versus environmental influences on central lumbar spinal stenosis and to investigate disc degeneration and stature or bone development as possible genetic pathways. MethodsA classic twin study with multivariate analyses considering lumbar level and other covariates was conducted. The study sample comprised 598 male twins (147 monozygotic and 152 dizygotic pairs), 35-70 years of age, from the population-based Finnish Twin Cohort. The primary phenotypes were central lumbar stenosis as assessed qualitatively on magnetic resonance imaging (MRI) and quantitatively measured dural sac cross-sectional area. Additional phenotypes (to examine possible genetic pathways) included disc bulging and standing height, as an indicator of overall skeletal size or development. ResultsThe heritability estimate (h(2)) for qualitatively assessed central lumbar spinal stenosis on MRI was 66.9% (95% confidence interval [95% CI] 56.8, 74.5). The broad-sense heritability estimate for dural sac cross-sectional area was 81.2% (95% CI 74.5, 86.1), with a similar magnitude of genetic influences across lumbar levels (h(2) = 72.4-75.6). The additive genetic correlation of quantitatively assessed stenosis and disc bulging was extremely high. There was no indication of shared genetic influences between stenosis and stature. ConclusionCentral lumbar spinal stenosis and associated dural sac dimensions are highly genetic, and disc degeneration (bulging) appears to be one pathway through which genes influence spinal stenosis. (Less)

Systemic sclerosis (SSc) is a complex disease involving multiple genetic factors. A recent genome-wide association study (GWAS) indicated that CD247 was strongly associated with SSc, which was subsequently confirmed in a SSc cohort of European population. However, genetic heterogeneity in different ethnic populations may significantly impact the complex trait of SSc. The studies herein aimed to examine whether the SSc-associated SNP rs2056626 of CD247 identified in Caucasian is also associated with Han Chinese SSc. A Han Chinese cohort consisting of 387 SSc patients and 523 healthy controls were examined in the studies. TaqMan assays were performed to examine the SNP. Exact p-values were obtained (Fisher’s test) from 2x2 tables of allele counts and disease status. The results showed that there was no association between rs2056626 of CD247 and SSc or any SSc subtypes of Han Chinese. The negative results are important in understanding genetics of SSc in different ethnic populations, which further suggest complex nature of genetics of SSc.

Objective.To identify differentially expressed genes in peripheral blood cells (PBC) of patients with ankylosing spondylitis (AS) relative to healthy controls and controls with systemic inflammation.Methods.We investigated PBC samples of 16 patients with AS and 14 matched controls, in addition to systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) samples utilizing Illumina Human Ref-8 BeadChips. Candidate genes were confirmed using quantitative PCR. Subsequently, these genes were also validated in a separate sample of 27 patients with AS [before and after anti-tumor necrosis factor (anti-TNF) treatment] and 27 matched controls.Results.We identified 83 differentially expressed transcripts between AS patients and controls. This gene list was filtered through the lists of differentially expressed transcripts in SLE and SSc, which resulted in identification of 52 uniquely dysregulated transcripts in AS. Many of the differentially expressed genes belonged to Toll-like receptor (TLR) and related pathways.TLR4andTLR5were the only dysregulated TLR subtypes among AS patients. We confirmed the overexpression ofTLR4andTLR5in AS patients in comparison to controls (p = 0.012 and p = 0.006, respectively) and SLE (p = 0.002, p = 0.008) using quantitative PCR in the same sample. Similarly,TLR4(p = 0.007) andTLR5(p = 0.012) were significantly upregulated among the AS patients before anti-TNF treatment in the confirmatory sample.TLR4(p = 0.002) andTLR5(p = 0.025) decreased significantly after anti-TNF treatment.Conclusion.PBC gene expression profiling in AS shows an upregulation ofTLR4andTLR5.This supports the importance of TLR subtypes in the pathogenesis of AS that are responsible for the immune response to Gram-negative bacteria.

Objective. Although the incidence of dcSSc is higher in African-American and Hispanic populations compared with European Caucasian patients, it is not clear whether there are differences in subsequent disease course. Also, the potential impact of gender on the disease course of dcSSc is not well defined. Our objective was to assess the course of modified Rodnan skin score (MRSS), HAQ-disability index (HAQ-DI) and forced vital capacity per cent (FVC%) predicted between men vs women and three ethnic groups with dcSSc participating in three randomized clinical trials (RCTs). Method. Data from RCTs (n = 495) were pooled and analysed. Baseline characteristics were compared in men vs women and among ethnic groups. A linear mixed effects model was used to assess the predictors of MRSS, HAQ-DI and FVC%. The primary independent variables were time-in-study and its interaction with gender and ethnicity. The models were adjusted for other covariates that were significant at baseline between gender and ethnicity analyses. Results. Men had lower HAQI-DI scores compared with women (P

Objectives. SSc-associated gastrointestinal tract involvement (SSc-GIT) is an important predictor of depressive symptoms. University of California at Los Angeles Scleroderma Clinical trial Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0) is a 34-item valid instrument that captures GIT symptom severity and impact on quality of life. It has seven GI-specific scales and a total GIT score. The objectives were to assess: (i) whether there is an association between depressed mood with GI symptom scales as assessed by the UCLA SCTC GIT 2.0 instrument; and (ii) to explore which GI-specific symptom scales are associated with depressed mood in patients with SSc. Methods. One hundred and fifty-two patients with SSc completed the UCLA SCTC GIT 2.0 and the Center for Epidemiologic Studies Short Depression scale (CES-D10). Patients were divided into depressed (CES-D5 10) or non-depressed group (CES-D < 10) and compared using t-test or chi-square test. Multiple linear regression was used to determine associations between GI scales and depressed mood (CES-D). Results. Study participants were 84% female, 78% Caucasian and 40% had depressed mood (CES-D105 10). Patients with depressed mood had statistically worse GI scale scores (except fecal soilage) and worse total GIT score (P < 0.05). In the multivariable model reflux and constipation scales were independently associated with worse CES-D scores (P = 0.010.06) Conclusion. SSc-GIT involvement is associated with depressed mood. Reflux and constipation scales of UCLA-SCTC GIT 2.0 were independently associated with CES-D. Future studies should assess if treatment of GIT symptoms will improve depressed mood in patients with SSc-GIT.

Systemic sclerosis (SSc) is a multisystem autoimmune disease of connective tissue characterized by immune dysregulation, obliterative vasculopathy, and fibrosis of skin and internal organs (1–3). Using microarrays, 4 previous studies have investigated the transcript profiles of SSc peripheral blood (PB) cells or their subpopulations. We first reported that, compared with PB cells from controls, PB cells from patients with early SSc have a distinct transcript pattern that includes dysregulation of interferon (IFN)–inducible genes (4). This observation was replicated by other investigators in PB mononuclear cells (PBMCs) (5), monocytes, and CD4+ T cells (6) and PB cells (7) from SSc patients. None of those studies found a correlation between the IFN signature and the clinical or serologic subtypes of SSc. Due to the heterogeneity of SSc, those studies may not have been sufficiently powered to assess subtle clinical and serologic differences in the transcript profile. However, Bos et al (7) reported that the expression levels of 5 IFN-inducible gene transcripts measured by quantitative polymerase chain reaction (PCR) in an extended group of 43 SSc patients were higher in patients without anticentromere antibodies (ACAs). Several studies have shown a striking pattern of up-regulated type I IFN–inducible genes in PBMCs from patients with systemic lupus erythematosus (SLE) (8–10). In particular, the presence of anti-Ro, anti–U1 RNP, anti-Sm, and anti–double-stranded DNA (anti-dsDNA) is significantly associated with a high IFN score in SLE (11). SSc shares several similarities with SLE, such as autoantibodies directed against nuclear antigens, and in some patients, overlapping clinical features. At the gene level, there is emerging evidence that SSc and SLE share common genetic associations, such as IRF5 (12–14) and PTPN22 (15–17). The risk alleles of the IRF5 and PTPN22 genes have been linked to higher serum levels of IFNα in SLE patients (18,19). Despite the evidence of similarities between SSc and SLE, a direct comparison of the transcript profiles of patients with the 2 diseases has not been undertaken. We now report the results of such a comparative study of a large number of SSc patients with SLE patients and controls. We analyzed our results using conventional methods and a newly described modular analysis framework (10). We examined whether SSc patients with certain genetic, clinical, or serologic features are more likely to have a transcript profile that is similar to that of SLE. The results place a subset of SSc patients alongside SLE in the continuum of IFN-mediated autoimmune diseases.

All authors: Olga Y. Gorlova , Yafang Li, Ivan Gorlov, Jun Ying, Wei V. Chen, Shervin Assassi, John D. Reveille, Frank C. Arnett, Xiaodong Zhou, Lara Bossini-Castillo, Elena Lopez-Isac, Marialbert Acosta-Herrera, Peter K. Gregersen, Annette T. Lee, Virginia D. Steen, Barri J. Fessler, Dinesh Khanna, Elena Schiopu, Richard M. Silver, Jerry A. Molitor, Daniel E. Furst, Suzanne Kafaja, Robert W. Simms, Robert A. Lafyatis, Patricia Carreira, Carmen Pilar Simeon, Ivan Castellvi, Emma Beltran, Norberto Ortego, Christopher I. Amos, Javier Martin, Maureen D. Mayes., Data Availability Statement: Genetic data is available from dbGaP repository (https://www.ncbi. nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_ id=phs000357.v1.p1)., Gene-level analysis of ImmunoChip or genome-wide association studies (GWAS) data has not been previously reported for systemic sclerosis (SSc, scleroderma). The objective of this study was to analyze genetic susceptibility loci in SSc at the gene level and to determine if the detected associations were shared in African-American and White populations, using data from ImmunoChip and GWAS genotyping studies. The White sample included 1833 cases and 3466 controls (956 cases and 2741 controls from the US and 877 cases and 725 controls from Spain) and the African American sample, 291 cases and 260 controls. In both Whites and African Americans, we performed a gene-level analysis that integrates association statistics in a gene possibly harboring multiple SNPs with weak effect on disease risk, using Versatile Gene-based Association Study (VEGAS) software. The SNP-level analysis was performed using PLINK v.1.07. We identified 4 novel candidate genes (STAT1, FCGR2C, NIPSNAP3B, and SCT) significantly associated and 4 genes (SERBP1, PINX1, TMEM175 and EXOC2) suggestively associated with SSc in the gene level analysis in White patients. As an exploratory analysis we compared the results on Whites with those from African Americans. Of previously established susceptibility genes identified in Whites, only TNFAIP3 was significant at the nominal level (p = 6.13x10-3) in African Americans in the gene-level analysis of the ImmunoChip data. Among the top suggestive novel genes identified in Whites based on the ImmunoChip data, FCGR2C and PINX1 were only nominally significant in African Americans (p = 0.016 and p = 0.028, respectively), while among the top novel genes identified in the gene-level analysis in African Americans, UNC5C (p = 5.57x10-4) and CLEC16A (p = 0.0463) were also nominally significant in Whites. We also present the gene-level analysis of SSc clinical and autoantibody phenotypes among Whites. Our findings need to be validated by independent studies, particularly due to the limited sample size of African Americans., Funding was provided to MDM by the National Institutes of Health (NIH) the National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS https://www.niams.nih.gov/) Centers of Research Translation (CORT) P50-AR054144, NIH grant N01-AR-02251 and R01-AR-055258, and the Department of Defense (DD) Congressionally Directed Medical Research Program (http://cdmrp.army.mil/) W81XWH-07-1-011 and WX81XWH-13-1-0452 for the collection, analysis and interpretation of the data.

Contains fulltext : 88471.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To investigate the possible association of the BANK1 gene with genetic susceptibility to systemic sclerosis (SSc) and its subphenotypes. METHODS: A large multicentre case-control association study including 2380 patients with SSc and 3270 healthy controls from six independent case-control sets of Caucasian ancestry (American, Spanish, Dutch, German, Swedish and Italian) was conducted. Three putative functional BANK1 polymorphisms (rs17266594 T/C, rs10516487 G/A, rs3733197 G/A) were selected as genetic markers and genotyped by Taqman 5 allelic discrimination assay. RESULTS: A significant association of the rs10516487 G and rs17266594 T alleles with SSc susceptibility was observed (pooled OR=1.12, 95% CI 1.03 to 1.22; p=0.01 and pooled OR=1.14, 95% CI 1.05 to 1.25; p=0.003, respectively), whereas the rs3733197 genetic variant showed no statistically significant deviation. Stratification for cutaneous SSc phenotype showed that the BANK1 rs10516487 G, rs17266594 T and rs3733197 G alleles were strongly associated with susceptibility to diffuse SSc (dcSSc) (pooled OR=1.20, 95% CI 1.05 to 1.37, p=0.005; pooled OR=1.23, 95% CI 1.08 to 1.41, p=0.001; pooled OR=1.15, 95% CI 1.02 to 1.31, p=0.02, respectively). Similarly, stratification for specific SSc autoantibodies showed that the association of BANK1 rs10516487, rs17266594 and rs3733197 polymorphisms was restricted to the subgroup of patients carrying anti-topoisomerase I antibodies (pooled OR=1.20, 95% CI 1.02 to 1.41, p=0.03; pooled OR=1.24, 95% CI 1.05 to 1.46, p=0.01; pooled OR=1.26, 95% CI 1.07 to 1.47, p=0.004, respectively). CONCLUSION: The results suggest that the BANK1 gene confers susceptibility to SSc in general, and specifically to the dcSSc and anti-topoisomerase I antibody subsets. 01 april 2010

Objective Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. Dysregulation of the immune system, including the Th1/Th2 cytokine balance, is central to the pathogenesis of SSc. This study was undertaken to investigate the hypothesis that single-nucleotide polymorphisms (SNPs) in TBX21 and STAT4, both of which are critical transcription factors that regulate the Th1/Th2 balance, are associated with SSc susceptibility. Methods We tested SNPs in TBX21 and STAT4 for association with SSc in 2 independent cohorts, the SSc Registry cohort (880 SSc cases and 507 controls) and the University of Texas SSc cohort (522 cases and 531 controls). Additional white control genotypes were obtained from public repositories. We also investigated for gene–gene interactions. Plasma cytokines and whole blood gene expression profiles were examined to determine functional effects of these SNPs. Results Multiple SNPs in TBX21 and STAT4 were found to be associated with SSc. In a combined analysis of 902 SSc patients and 4,745 controls, TT genotyping of the TBX21 rs11650354 variant revealed a recessive pattern for disease susceptibility (Pcorr = 1.4 × 10−15, odds ratio 3.37, 95% confidence interval 2.4–4.6). In an analysis of 1,039 SSc patients and 3,322 controls, the A allele of the STAT4 variant rs11889341 was associated with increased SSc susceptibility in a dominant pattern (Pcorr = 2.4 × 10−5, odds ratio 1.29, 95% confidence interval 1.2–1.5). Furthermore, we identified gene–gene interaction among the TBX21 and STAT4 variants, such that the STAT4 genotype increased the risk of SSc only in the TBX21 CC genotype group. SSc patients carrying the TBX21 CC genotype had higher interleukin-6 (IL-6) and tumor necrosis factor α levels, and those with the TT genotype had elevated IL-2, IL-5, IL-4, and IL-13 (Th2) levels, compared with controls. Whole blood expression profiles revealed dysregulation of type I interferon pathways in the CC group and T cell pathways in the TT group of the TBX21 SNP. Conclusion The present results, from studies of 2 independent cohorts, indicate that SNPs in TBX21 and STAT4 contribute uniquely and interactively to SSc susceptibility, leading to altered cytokine balance and immune dysregulation.

To identify systemic sclerosis (SSc) susceptibility loci via a genome-wide association study.A genome-wide association study was performed in 137 patients with SSc and 564 controls from Korea using the Affymetrix Human SNP Array 5.0. After fine-mapping studies, the results were replicated in 1,107 SSc patients and 2,747 controls from a US Caucasian population.The single-nucleotide polymorphisms (SNPs) (rs3128930, rs7763822, rs7764491, rs3117230, and rs3128965) of HLA-DPB1 and DPB2 on chromosome 6 formed a distinctive peak with log P values for association with SSc susceptibility (P=8.16x10(-13)). Subtyping analysis of HLA-DPB1 showed that DPB1*1301 (P=7.61x10(-8)) and DPB1*0901 (P=2.55x10(-5)) were the subtypes most susceptible to SSc in Korean subjects. In US Caucasians, 2 pairs of SNPs, rs7763822/rs7764491 and rs3117230/rs3128965, showed strong association with SSc patients who had either circulating anti-DNA topoisomerase I (P=7.58x10(-17)/4.84x10(-16)) or anticentromere autoantibodies (P=1.12x10(-3)/3.2x10(-5)), respectively.The results of our genome-wide association study in Korean subjects indicate that the region of HLA-DPB1 and DPB2 contains the loci most susceptible to SSc in a Korean population. The confirmatory studies in US Caucasians indicate that specific SNPs of HLA-DPB1 and/or DPB2 are strongly associated with US Caucasian patients with SSc who are positive for anti-DNA topoisomerase I or anticentromere autoantibodies.

We describe a novel approach to genetic association analyses with proteins sub-divided into biologically relevant smaller sequence features (SFs), and their variant types (VTs). SFVT analyses are particularly informative for study of highly polymorphic proteins such as the human leukocyte antigen (HLA), given the nature of its genetic variation: the high level of polymorphism, the pattern of amino acid variability, and that most HLA variation occurs at functionally important sites, as well as its known role in organ transplant rejection, autoimmune disease development and response to infection. Further, combinations of variable amino acid sites shared by several HLA alleles (shared epitopes) are most likely better descriptors of the actual causative genetic variants. In a cohort of systemic sclerosis patients/controls, SFVT analysis shows that a combination of SFs implicating specific amino acid residues in peptide binding pockets 4 and 7 of HLA-DRB1 explains much of the molecular determinant of risk.

Objective.To measure self-reported physical and mental functioning and associated clinical features at study entry in 3 ethnic groups with systemic sclerosis (SSc).Methods.Sixty Hispanic, 39 African American, and 104 Caucasian patients with recent-onset SSc (< 5 yrs) were assessed for perceived physical and mental functioning, using the Medical Outcomes Study Short Form-36 (SF-36) and Scleroderma-Health Assessment Questionnaire (Scleroderma-HAQ). Socioeconomic, demographic, clinical, immunologic, immunogenetic, behavioral, and psychological variables (Interpersonal Support Evaluation List, ISEL; Illness Behavior Questionnaire, IBQ; and Arthritis Helplessness Index, AHI) were analyzed by linear regression models for associations with SF-36 and mHAQ scores as dependent variables.Results.Perceived physical functioning scores had ethnic-specific associations with AHI > fatigue scores > IBQ > clinical variables (hypertension, skin score, and percentage predicted DLCO). Scleroderma-HAQ scores had ethnic-specific associations with IBQ > AHI scores > most clinical and laboratory variables. Decreased mental component summary (MCS) scores associated with AHI > ISEL. Ethnic-specific immunogenetic variables HLA-DQB1*0202 (Caucasian) and HLA-DRB 1*11 (African American), and HLA-DQA1*0501 (Hispanic) also associated with MCS. Antinuclear autoantibodies, anti-topoisomerase I, and RNA polymerases I and III also demonstrated associations with functioning in African American and Hispanic groups.Conclusion.Clinical, psychosocial, and immunogenetic variables had ethnic-specific associations with perceived physical and mental functioning. Consideration of ethnic-specific psychological and behavioral support in designing more personalized, relevant therapeutic interventions for the patient may improve therapeutic efficacy in SSc.

Objective To investigate the clinical and genetic variables at initial presentation that predict survival in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) cohort. Methods GENISOS is a prospective, observational study of a multiethnic early systemic sclerosis (SSc) cohort. To date, a total of 250 patients have been enrolled. In addition to clinical and laboratory data, electrocardiograms (EKGs), chest radiographs, and pulmonary function tests have been obtained from each patient. A modified Rodnan skin thickness score, HLA class II genotyping, and a Medsger Damage Index also have been collected. We performed multivariable analyses utilizing the Cox regression following a purposeful model building strategy. Results The study analyzed 122 white, 47 African American, and 71 Hispanic SSc patients with an average disease duration of 2.6 years at enrollment. At the time of analysis, 52 (20.8%) of the 250 patients had died. In the final multivariable model excluding HLA genes, 7 variables emerged as significant predictors of mortality: age ≥65 years at enrollment, forced vital capacity

ObjectiveIt is increasingly being appreciated that multiple autoimmune diseases share common susceptibility genes. The tumour necrosis factor ligand superfamily member 4 gene (TNFSF4, OX40L), which encodes for the T cell costimulatory molecule OX40 ligand, has been identified as a susceptibility gene for the development of systemic lupus erythematosus (SLE). Accordingly, the aim of the current study was to investigate the possible association of the TNFSF4 gene region with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis.MethodsA total of 9 single nucleotide polymorphisms (SNPs) in the TNFSF4 gene region, previously associated with susceptibility to SLE, were tested for association with SSc in a collection of 1059 patients with SSc and 698 controls.ResultsCase-control comparisons revealed a significant association between susceptibility to SSc and the minor alleles at SNPs rs1234314 (OR 1.20, 95% CI 1.04 to 1.4, pFDR=0.019), rs2205960 (OR 1.24, 95% CI 1.10 to 1.50, pFDR=0.019) and rs844648 (OR 1.16, 95% CI 1.01 to 1.30, pFDR=0.032). The minor allele at rs844644 was protective (OR 0.84, 95% CI 0.70 to 0.97, pFDR=0.038). Analysis of subsets of patients with SSc demonstrated significant associations of the TNFSF4 SNPs with limited and diffuse SSc as well as specific SNPs that were associated with SSc-associated autoantibodies. Finally, the analyses suggest a potential interaction between two TNFSF4 SNPs, rs2205960 and rs844648, with regards to SSc susceptibility.ConclusionsPolymorphisms in the TNFSF4 gene region are associated with susceptibility to SSc and its clinical and autoantibody subsets. TNFSF4 may be another gene that confers risk to multiple autoimmune diseases.

Objective. To refine the previously developed scleroderma (systemic sclerosis [SSc]) gastrointestinal tract (GIT) instrument (SSC-GIT 1.0). Methods. We administered the SSC-GIT 1.0 and the Short Form 36 to 152 patients with SSc; 1 item was added to the SSC-GIT 1.0 to assess rectal incontinence. In addition, subjects completed a rating of the severity of their GIT involvement (from very mild to very severe). Evaluation of psychometric properties included internal consistency reliability, test– retest reliability (mean time interval 1.1 weeks), and multitrait scaling analysis. Results. Study participants were mostly women (84%) and white (81%); 55% had diffuse SSc. Self-rated severity of GIT involvement ranged from no symptoms to very mild (39%), mild (21%), moderate (31%), and severe/very severe (9%). Of an initial 53 items in the SSC-GIT 1.0, 19 items were excluded, leaving a 34-item revised instrument (the University of California, Los Angeles Scleroderma Clinical Trial Consortium GIT 2.0 [UCLA SCTC GIT 2.0]). Analyses supported 7 multi-item scales: reflux, distention/bloating, diarrhea, fecal soilage, constipation, emotional well-being, and social functioning. Test–retest reliability estimates were >0.68 and coefficient alphas were >0.67. Participants who rated their GIT disease as mild had lower scores on a 0 –3 scale on all 7 scales. Symptom scales were also able to discriminate subjects with corresponding clinical GIT diagnoses. The Total GIT Score, developed by averaging 6 of 7 scales (excluding constipation), was reliable and provided greater discrimination between mild, moderate, and severe self-rated GIT involvement than individual scales. Conclusion. This study provides support for the reliability and validity of the UCLA SCTC GIT 2.0, an improvement over the SSC-GIT 1.0, and supports a Total GIT Score in SSc patients with GIT.

Objective A phase II randomized controlled trial of recombinant human relaxin suggested that a dosage of 25 μg/kg/day was safe and clinically effective in improving skin disease and reducing functional disability in scleroderma (systemic sclerosis; SSc). We undertook a large randomized, double-blind, placebo-controlled clinical trial to compare placebo with 10 μg/kg/day and 25 μg/kg/day recombinant human relaxin, given for 24 weeks in patients with stable, diffuse, moderate-to-severe SSc. Methods Men and women ages 18–70 years with diffuse cutaneous SSc (dcSSc) were administered recombinant human relaxin (10 μg/kg/day or 25 μg/kg/day) or placebo for 24 weeks as a continuous subcutaneous infusion. There was a followup safety visit at week 28. Results The primary outcome measure, the modified Rodnan skin thickness score, was similar among the 3 groups at baseline and at weeks 4, 12, and 24. Secondary outcomes such as functional disability were similar in all 3 groups, while the forced vital capacity decreased significantly in the relaxin groups. The discontinuation of both doses of relaxin at week 24 led to statistically significant declines in creatinine clearance and serious renal adverse events (defined as doubling of serum creatinine, renal crisis, or grade 3 or 4 essential hypertension) in 7 patients who had received relaxin therapy but in none who had received placebo. Conclusion Recombinant relaxin was not significantly better than placebo in improving the total skin score or pulmonary function or in reducing functional disability in patients with dcSSc. In addition, relaxin was associated with serious renal adverse events, the majority of which occurred after stopping the infusion. If relaxin is used therapeutically for any conditions other than scleroderma, close monitoring of blood pressure and renal function must be performed.

Objective Gastrointestinal tract (GIT) involvement occurs in ∼90% of patients with systemic sclerosis (SSc) and has a major impact on health-related quality of life (HRQOL). We developed an HRQOL instrument for persons with SSc. Methods The Scleroderma Gastrointestinal Tract 1.0 (SSC-GIT 1.0) survey was developed after an extensive literature search, solicitation and consideration of experts' opinions, and 2 focus groups of 16 subjects with SSc and GIT involvement. A 75-item, self-reported measure assessing bowel involvement, emotional well-being, and social functioning was administered to subjects with SSc and GIT involvement. Also, subjects completed the Short Form 36 and rated the severity of their GIT symptoms (very mild to very severe), and items were transformed linearly to a scale with a possible range of 0 (worse health) to 100 (better health). Evaluation of psychometric properties included internal consistency reliability, test–retest reliability (1.3-week median time interval), multitrait scaling analysis, and exploratory factor analysis. Results Study participants (n = 88) were primarily female (95.5%), white (79.3%), and had a mean age of 52.4 years. Self-rated severity of GIT involvement ranged from very mild or mild (36.0%) to moderate (44.0%) to severe or very severe (20.0%). Of 75 items, 23 had low item-total correlations (≤0.39) and were excluded, leaving a 52-item instrument. Analyses supported 6 multi-item HRQOL scales: reflux/indigestion, diarrhea, constipation, pain, emotional well-being, and social functioning. Test–retest reliability estimates ranged 0.69–0.90 and Cronbach's alpha ranged 0.69–0.93. Participants who rated their GIT disease as mild had the highest scores (better health) on all 6 scales; participants who rated their GIT as severe had the lowest scores (poor health). Conclusion The results support the reliability and validity of the SSC-GIT 1.0 as a measure of SSc GIT involvement. Further research is needed to examine the ability to detect change over time and define minimally important differences.

Objective To determine the relative contributions of genetic, clinical, serologic, sociodemographic, and behavioral/psychological variables to early pulmonary involvement in the Genetics versus Environment in Scleroderma Outcome Study cohort. Methods At the baseline visit (V0), 203 patients with systemic sclerosis (SSc) were examined (104 whites, 39 African Americans, and 60 Hispanics). We obtained sociodemographic, behavioral/psychological (illness behavior, social support, learned helplessness, smoking, drinking), clinical, serologic (autoantibodies), and genetic (HLA class II and FBN1 genotypes) factors; pulmonary function test results; electrocardiograms; and chest radiographs. Data analysis included Fisher's exact test, chi-square test, Student's t-test, analysis of variance, and stepwise linear and logistic regression methods. Results Significant pulmonary involvement was seen in 25% of patients within 2.8 years of SSc diagnosis. At V0, pulmonary fibrosis was significantly higher in African Americans compared with whites or Hispanics. African Americans had significantly lower percent predicted forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) compared with whites and significantly lower percent predicted diffusing capacity for carbon monoxide (DLCO) compared with whites and Hispanics. Significant, independent associations impacting early pulmonary involvement included African American ethnicity, skin score, serum creatinine and creatine phosphokinase values, hypothyroidism, and cardiac involvement. Anticentromere antibody seropositivity was a significant, independent, protective factor for restrictive lung disease and FVC or DLCO values. African Americans had significantly increased frequencies of anti–topoisomerase I, fibrillarin, and RNP autoantibodies compared with whites. African Americans scored significantly lower on the Interpersonal Support Evaluation List and significantly higher on the Illness Behavior Questionnaire. Conclusion Early pulmonary involvement in SSc appears to be influenced by several factors delineated by ethnicity, including racial, socioeconomic, behavioral, and serologic determinants.

Objective To examine whether the affected first-degree relatives within multicase systemic sclerosis (SSc; scleroderma) families are concordant for autoantibody profile, disease type, and HLA class II haplotypes and whether clinical expression and serologic characteristics of familial SSc differ from those of sporadic SSc. Methods Seven hundred ten SSc families from the Scleroderma Family Registry and DNA Repository (Scleroderma Registry) were examined, and 18 multicase families were identified. SSc cases and their first-degree family members underwent serologic testing for different autoantibodies. The disease type and various disease features were abstracted from the available medical records. Additionally, HLA class II typing was performed on the multicase SSc sibpairs. Results The observed SSc-specific antibody concordance within each multicase SSc family was statistically more common than expected by chance alone (P = 0.007). The autoantibody profile and disease features of familial and sporadic SSc cases did not differ significantly. The frequency of autoantibody positivity was not different between unaffected first-degree family members of patients from multicase versus singleton SSc families. HLA haplotype sharing between SSc sibpairs was significantly more common than expected (P = 0.011). Conclusion The affected members within multicase SSc families tend to be concordant for SSc-specific autoantibodies and HLA haplotypes; familial SSc does not appear to be a unique disease subset.

Objective To assess the impact of cyclophosphamide (CYC) on the health-related quality of life (HRQOL) of patients with scleroderma after 12 months of treatment. Methods One hundred fifty-eight subjects participated in the Scleroderma Lung Study, with 79 each randomized to CYC and placebo arms. The study evaluated the results of 3 measures of health status: the Short Form 36 (SF-36), the Health Assessment Questionnaire (HAQ) disability index (DI), and Mahler's dyspnea index, and the results of 1 preference-based measure, the SF-6D. The differences in the HRQOL between the 2 groups at 12 months were calculated using a linear mixed model. Responsiveness was evaluated using the effect size. The proportion of subjects in each treatment group whose scores improved at least as much as or more than the minimum clinically important difference (MCID) in HRQOL measures was assessed. Results After adjustment for baseline scores, differences in the HAQ DI, SF-36 role physical, general health, vitality, role emotional, mental health scales, and SF-36 mental component summary (MCS) score were statistically significant for CYC versus placebo (P < 0.05). Effect sizes were negligible (

To examine the heterogeneity of global transcriptome patterns in systemic sclerosis (SSc) skin in a large sample of patients with SSc and control subjects.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.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.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.

Autoantibodies directed against the two principal antigens of the human exosome complex, PM75 and PM100, are present in systemic sclerosis (SSc) sera and have been associated with myositis and calcinosis. However, there is a paucity of data on the clinical correlates of these autoantibodies separately and in the absence of other SSc-specific antibodies. The aim of this study was to assess the clinical correlates of monospecific anti-PM75 and anti-PM100 in SSc.A tri-nation cohort of 1574 SSc subjects was formed, clinical variables were harmonized and sera were tested for anti-PM75 and anti-PM100 antibodies using a line immunoassay.Forty-eight (3.0%) subjects had antibodies against PM75 and 18 (1.1%) against PM100. However, only 16 (1%) had monospecific anti-PM75 antibodies and 11 (0.7%) monospecific anti-PM100 antibodies (i.e. in isolation of each other and other SSc-specific antibodies). Monospecific profiles of each autoantibody included more calcinosis. An increased frequency of myositis was only seen in subjects positive for both anti-PM75 and anti-PM100 antibodies. Lung disease was only associated with anti-PM75 and subjects with anti-PM100 antibodies had better survival compared to other antibody subsets.The prevalence of monospecific anti-PM75 and anti-PM100 antibodies in this large SSc cohort was low. Disease features associated with anti-PM/Scl antibodies may depend on particular and possibly multiple antigen specificities. However, due to the small samples, these results need to be interpreted with caution. International collaborations are key to understanding the clinical correlates of uncommon serological profiles in SSc.

Objective.Autoantibodies to the dense fine speckled 70 kDa antigen (DFS70) are reported to be more common in individuals who do not have an antinuclear antibody (ANA)-associated rheumatic disease (AARD) than in patients with AARD. The frequency of anti-DFS70 antibodies has been thoroughly studied in adult but not in pediatric populations. The primary objective of this observational study was to determine the frequency of anti-DFS70 in pediatric AARD and reference cohorts.Methods.Sera from 743 children with AARD and related conditions, and 345 samples from reference cohorts (healthy children and those being investigated for AARD) were studied for anti-DFS70 autoantibodies as measured by a chemiluminescence immunoassay. A de-identified administrative database was used to retrieve demographic, serologic, and clinical data.Results.Anti-DFS70 antibodies were seen in 2.1% of healthy children and in 4.5% of sera from pediatric individuals referred for ANA testing. The frequency of anti-DFS70 was highest in juvenile localized scleroderma (LS; 4/29, 13.8%), juvenile dermatomyositis (JDM; 2/11, 18.2%), childhood systemic lupus erythematosus (cSLE; 19/331, 5.7%), diffuse cutaneous systemic sclerosis (1/22, 4.5%), celiac disease (2/49, 4.1%), and juvenile idiopathic arthritis (JIA; 5/202, 2.5%). Of note, anti-DFS70 antibodies were observed in 3/26 children (11.5%) with uveitis and JIA-associated uveitis.Conclusion.The frequency of anti-DFS70 autoantibodies in healthy pediatric subjects is within the lower range of that reported in adults. Anti-DFS70 antibodies can be found in childhood SSc and cSLE, but has a remarkably high frequency in children with LS, JDM, and uveitis.

OBJECTIVE. Systemic sclerosis (SSc) is a rare disease that is particularly uncommon in children. Specific HLA alleles have been associated with SSc in adults. This study was undertaken to investigate HLA class II alleles in juvenile-onset SSc. METHODS. DRB1, DQA1, and DQB1 alleles were determined by DNA-based HLA typing. Analyses were conducted comparing Caucasian patients with juvenileonset SSc (n = 76) to healthy Caucasian controls (n = 581). RESULTS. Initial analyses focused on HLA class II associations previously reported in adult Caucasian patients with SSc. The frequency of DRB1*11 was not significantly increased in juvenile-onset SSc (22.4% of patients with juvenile-onset SSc versus 17.6% of controls; odds ratio [OR] 1.35, P = 0.34), nor were the specific DRB1*11:01 or *11:04 alleles. DQA1*05, a risk factor previously identified in adult men with SSc, was increased in patients with juvenile-onset SSc versus controls (57.9% versus 44.1%; OR 1.76, P = 0.027), as was DRB1*03 (34.2% versus 22.5%; OR 1.79, P = 0.031). Secondary analyses of all DRB1 allele groups revealed an association with DRB1*10 (10.5% of patients with juvenile-onset SSc versus 1.5% of controls; OR 7.48, P = 0.0002). As this is a new observation, correction was made for multiple comparisons of 13 different DRB1 allele groups; results nevertheless remained significant (P = 0.003). Also, a lower frequency of DRB1*01 was observed in patients with juvenile-onset SSc who were younger at disease onset (OR 0.06, P = 0.01) and in those with antibodies to topoisomerase (OR 0.14, P = 0.024). CONCLUSION. Associations of HLA alleles with juvenile-onset SSc differed from associations with SSc in women, but were similar to associations with SSc in men. Additionally, a novel association with DRB1*10 was observed in children. The greatest proportion of genetic risk of SSc is contributed by the HLA complex, and the current study reveals the importance of the association of HLA class II genes in juvenile-onset SSc.

Systemic sclerosis (SSc) is connective tissue disorder in which fibrosis of the skin and internal organs is the main hallmark. Despite the difficulties of studying a complex disease, significant advances have been achieved in the SSc genetics field. In this review, we will describe the firmest genetic susceptibility markers known to date. We will analyze the most recent findings in the HLA region and in non-HLA genes. Furthermore, we will propose functional connections of these loci with the mechanisms involved in SSc pathogenesis. However, only non-HLA genetic regions that have been associated with SSc at the genome-wide significance level or that have been reported to be associated with the disease in at least two different independent studies will be considered. In spite of the increasing number of SSc genetic susceptibility factors identified, further studies with larger sample sizes, deeper phenotype characterization of the patients and innovative analyses will be needed to translate SSc genetics into clinical practice and patient care in the future.

Systemic sclerosis (SSc) is a rare autoimmune disease characterized by autoantibody production, small-vessel vasculopathy, and skin and other organ fibrosis. The disease is clinically heterogeneous with most patients having some degree of skin sclerosis with varying organ system involvement. Early disease can be difficult to diagnose, especially with minimal skin sclerosis and absence of anti-nuclear antibody (ANA) positivity; however, studies have demonstrated early diagnosis is important as early treatment could potentially lead to better outcomes. New classification criteria have recently been published that have higher sensitivity for detecting early disease thus allowing for a broader spectrum of patients to be represented in clinical trials. Treatment guidelines have been published based on a limited number of randomized-controlled clinical trials; however, there are ongoing phase II and III clinical trials with novel agents that are promising and will change the treatment landscape over the next decade.

Autoantibodies directed against Ro52/TRIM21 are common in systemic sclerosis (SSc) but their clinical significance remains uncertain. The aim of this study was to assess the clinical correlates and survival of subjects with monospecific anti-Ro52/TRIM21 antibodies, i.e. anti-Ro52/TRIM21 antibodies in the absence of other SSc-related antibodies.A tri-nation (Canada, Australia, USA) cohort of 1574 SSc subjects was formed, demographic and clinical variables were harmonised and sera were tested using a common diagnostic platform. Statistical analyses were performed to determine associations between the presence of monospecific anti-Ro52/TRIM21 antibodies and outcomes of interest, including interstitial lung disease (ILD) and survival.103 (6.5%) had monospecific anti-Ro52/TRIM21 antibodies, 324 (20.6%) had anti-Ro52/TRIM21 antibodies overlapping with other SSc-related antibodies and 1147 (72.9%) were negative for anti-Ro52/TRIM21 antibodies. Monospecific subjects were less likely to be White compared to negative subjects (68% vs. 82%, odds ratio (OR) 0.48, 95% confidence interval (CI) 0.30-0.75, p=0.0011). ILD was the only clinical variable significantly associated with monospecific anti-Ro52/TRIM21 antibodies compared to negative subjects (adjusted OR 2.70, 95% CI 1.75-4.14, p0.0001). Subjects with monospecific anti-Ro52/TRIM21 antibodies were at significantly increased risk of death compared to subjects without anti-Ro52/TRIM21 antibodies (log rank p=0.0003; adjusted hazard ratio (HR) 1.87, 95% CI 1.24-2.82, p=0.0029).The results obtained from this unique tri-nation cohort represent the strongest evidence to date that anti-Ro52/TRIM21 antibodies are independently associated with the presence of ILD and poor survival in SSc. These data provide strong support for the predictive and prognostic value of this serological biomarker in SSc.

BACKGROUND We conducted a double-blind, randomized, placebo-controlled trial to determine the effects of oral cyclophosphamide on lung function and health-related symptoms in patients with evidence of active alveolitis and scleroderma-related interstitial lung disease. METHODS At 13 clinical centers throughout the United States, we enrolled 158 patients with scleroderma, restrictive lung physiology, dyspnea, and evidence of inflammatory interstitial lung disease on examination of bronchoalveolar-lavage fluid, thoracic highresolution computed tomography, or both. Patients received oral cyclophosphamide (≤2 mg per kilogram of body weight per day) or matching placebo for one year and were followed for an additional year. Pulmonary function was assessed every three months during the first year, and the primary end point was the forced vital capacity (FVC, expressed as a percentage of the predicted value) at 12 months, after adjustment for the baseline FVC. RESULTS Of 158 patients, 145 completed at least six months of treatment and were included in the analysis. The mean absolute difference in adjusted 12-month FVC percent predicted between the cyclophosphamide and placebo groups was 2.53 percent (95 percent confidence interval, 0.28 to 4.79 percent), favoring cyclophosphamide (P

Parents of 26 children With diagnoses of Asperger's disorder completed a symptom checklist to determine Whether the children met Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition, Text Revision (DSM-IV-TR; American Psychiatric Association, 2000) criteria for Asperger's disorder, autism, or pervasive developmental disorder not otherWise specified. Results shoWed that almost all (20) met criteria for autism, and a DSM-IV-TR diagnosis of Asperger's disorder could not be confirmed in any child. Further, 95% of the parents Whose children did not have a DSM-IV-TR diagnosis of Asperger's disorder agreed With their child's diagnosis of Asperger's disorder. Our findings suggest that the hierarchical DSM-IV-TR criteria are not applied by clinicians to diagnose Asperger's disorder because most children With diagnoses of Asperger's disorder actually met DSM-IV-TR criteria for autism, Which precludes a diagnosis of Asperger's disorder. These findings are consistent With previous studies. Most experts noW agree that autism is a spectrum disorder and Asperger's disorder is actually high-functioning autism. Implications for the next revision of the DSM are discussed.

OBJECTIVE To obtain a global view of the immunological alterations occurring in early systemic sclerosis (SSc) by transcriptional profiling of peripheral blood cells (PBCs). METHODS Oligonucleotide microarrays were used to compare PBC gene expression profiles in 18 SSc cases (

Objective Most of the data about the prevalence of pulmonary arterial hypertension (PAH) are from tertiary centers that are biased toward seeing more severe cases; therefore, the true prevalence of PAH among patients with connective tissue disease is unknown. We sought to determine the point prevalence of undiagnosed PAH in community-based rheumatology practices. Methods The study design was a multicenter, prospective and retrospective survey and analysis of clinical cases in 50 community rheumatology practices. We evaluated a total of 909 patients with either scleroderma (systemic sclerosis [SSc]) or mixed connective tissue disease (MCTD). If a subject had not been diagnosed as having PAH, then a new Doppler echocardiogram was obtained to measure cardiac parameters, including estimated right ventricular systolic pressure (ERVSP), and a full review of medical records was done. Results Of 909 screened patients, 791 were evaluable and completed the study; 669 had not previously been studied for PAH. Of these 669 patients, 89 (13.3%) were found by Doppler echocardiography to have an ERVSP of ≥40 mm Hg. Of these 89 patients, 82 (92.1%) had SSc and 7 (7.9%) had MCTD. The total prevalence of PAH in the survey was 26.7% (211 of 791 patients, including 122 with known PAH and 89 newly diagnosed as having PAH). Doppler echocardiographic data showed 20 of 89 patients (22.5%) with ERVSP of ≥50 mm Hg, 20 of 89 patients (22.5%) with increased RV dimension, and 25 of 89 patients (28.1%) with right atrial enlargement. Patients with ERVSP ≥40 mm Hg had decreased exercise tolerance compared with those with ERVSP

Objective To determine whether baseline self-assessment measures of health status and physiologic indices of disease severity in alveolitis-positive patients with systemic sclerosis (SSc) correlate with the severity of their dyspnea, and to quantify functional impairment in patients with scleroderma lung disease and compare it with that in patients with chronic obstructive pulmonary disease (COPD). Methods SSc patients (n = 138) with diffuse (n = 81) or limited (n = 57) cutaneous disease and active alveolitis (determined by bronchoalveolar lavage and/or high-resolution computed tomography) who participated in the National Heart, Lung, and Blood Institute–sponsored, multicenter, parallel-group, double-blind, randomized, placebo-controlled trial of oral cyclophosphamide for treatment of SSc-associated interstitial lung disease were evaluated. Pearson's univariate correlations were determined between the Short Form 36 (SF-36) physical component summary (PCS) and mental component summary (MCS) scales, functional questionnaires, and physiologic parameters of breathing (forced vital capacity [FVC] and single-breath diffusing capacity for carbon monoxide [DLCO]). Student's t-test was used to compare subgroups. Scores from 2 instruments for self-assessment of breathlessness, Mahler's baseline dyspnea index (BDI) and a visual analog scale (VAS) for breathing, were divided at the median. Values for the DLCO and FVC (% predicted) were divided based on the American Thoracic Society guidelines for mild (>70% of predicted), moderate (50–70% of predicted), and severe (

Objective To determine the incidence of cancer in patients with scleroderma (systemic sclerosis) and to compare those rates with cancer rates in the local population. Methods Cancer risk in scleroderma patients in the Detroit metropolitan area was assessed by linking patient identification codes of the Michigan Scleroderma Registry to the Metropolitan Detroit Cancer Surveillance System database. Patients were screened between the years 1973 and 2002, with additional followup to 2004. Standardized incidence ratios (SIRs) were calculated for selected malignancies (lung, liver, colon, breast, cervical, and prostate cancers, and non-Hodgkin's lymphomas), with stratification by sex and race. Results Of 934 patients in the Scleroderma Registry, 538 were included in the study based on tri-county residency (436 females and 102 males). Of these, 45 first malignancies were noted (37 females and 8 males). Lung cancer (10 cases) was found to be the most common cancer in scleroderma patients. However, its incidence was not significantly different from that in the general population of metropolitan Detroit (SIR 1.23). Other types of cancer were examined, and no significant differences were found as compared with the rates in the local population, with 1 exception: black females with scleroderma had significantly higher rates of liver cancer (SIR 45.8). Conclusion Contrary to previous studies, this study did not find statistical evidence of an increased incidence of cancer in scleroderma patients, except for liver cancer. One possible reason is the high background rates of certain cancers in the metropolitan Detroit area. It may be necessary to consider local cancer rates when comparing different scleroderma cohorts.

Background: Two carotenoids, lutein and zeaxanthin are found in the retinal pigment epithelium of the eye where they are believed to protect it against oxidative and light damage. The amounts of these carotenoids consumed by premature infants are not known. Objectives: The objective of the investigation was to measure these carotenoids in human and formulae milks. Design: In all, 28 human milk samples were obtained at various times between days 1 and 41 of lactation from 13 mothers. Six formula milks commonly used in hospitals were also analysed. Setting: Mothers who provided the milk samples had infants in the neonatal ward at the Royal Maternity Hospital, Belfast. Results: Median lutein and zeaxanthin concentrations in human milk were 4.79 (range 0.42–9.98) nmol/g fat and 0.55 (0.00–1.70) nmol/g fat, respectively. Five of the six formula milks also contained lutein and zeaxanthin with concentrations that varied over a wide range (0.7–9.7 and 0.1–1.2 nmol/g fat, respectively). Conclusions: Carotenoid concentrations usually decreased with the duration of lactation. Some formula milks that were specially formulated for premature infants contained high concentrations of the lutein and zeaxanthin and the source may be egg yolk. Sponsorship: These studies were supported by the University of Ulster and the Northern Ireland Mother and Baby Appeal.

Evidence from multiple sources indicates that SSc does not occur randomly in the population; there are particular groups who are at greater risk. The overall incidence rate of SSc in the adult population of the United States is approximately 20 per million per year; this rate has increased from 1944 to 1973, but has been relatively stable since that time. The prevalence of SSc in the United States also seems to be stable over the past two decades with a prevalence estimate for adults of 240 per million. Recent population studies suggest that SSc occurs more frequently in the United States than in continental Europe, the United Kingdom, and in some areas in Asia. Overall survival has improved over the past few decades; mean survival is approximately 12 years from diagnosis. Renal disease accounts for some of the early mortality, but pulmonary disease has emerged as a major cause of death. Cardiac disease is also correlated with a poorer prognosis. Gastrointestinal involvement contributes to morbidity and, indirectly, to mortality, but the magnitude of this contribution is difficult to assess. Women are affected more frequently than men but the factors that are responsible for this are not apparent. Studies of reproductive history have provided conflicting data; some studies suggested that the number of pregnancies may influence later disease expression, whereas other studies found no correlation. Racial factors seem to play a role in disease susceptibility, as well as disease expression. Age-specific incidence rates are higher in black women than in white women; the greatest difference occurs in the young to middle adult age group (less than 54 years of age). Diffuse disease also seems to occur more commonly in the black population than in the white. Age at onset of diffuse disease is younger, on average, than the age at onset of limited disease; age-adjusted survival is worse in black women than in white women because of their predilection for diffuse disease. Reports of geographic clustering are intriguing; the reported clusters in London and Italy have not resulted in the identification of potential causal factors. The Choctaw Native American cluster suggests that genetic factors that have not been identified may play an important role. Familial clustering of SSc has been demonstrated in the United States and in Australia, which provides additional evidence of a genetic component. It is likely that there is a strong interplay among genetic factors, hormonal or reproductive-related events, and an external trigger that must interact to result in clinical disease.

Exposure to solvents has been reported to increase the risk of scleroderma. The authors investigated the relation between exposures to solvents in occupational and hobby settings and the development of scleroderma among women in a case-control study with population-based controls in Michigan (1980-1991) and Ohio (1980-1992). A total of 660 cases and 2,227 frequency-matched controls were interviewed by telephone. Diagnoses of scleroderma were verified by medical records review. Paint thinners and removers were significantly associated with scleroderma both by self-report (odds ratio (OR) = 1.9, 95% confidence interval (CI): 1.4, 2.6) and after expert review (OR = 2.0, 95% CI: 1.5, 2.6). Other petroleum distillates (gasoline and mineral spirits) were not significantly associated with scleroderma after controlling for other correlated exposures in multivariable analyses. Trichloroethylene was associated with scleroderma both by self-report (OR = 2.0, 95% CI: 0.8, 4.8) and after expert review (OR = 1.9, 95% CI: 0.6, 6.6), but not significantly. Analyses by duration of exposure found that risk increased with the duration of use of any of the solvents (OR = 1.01/year of exposure, 95% CI: 1.01, 1.02), but there was no evidence of increasing risk with increasing duration of exposure for any specific solvent studied. In summary, exposures to paint thinners and removers were associated with scleroderma in women but showed no evidence of increasing risk with increasing duration. Exposures to other specific chlorinated and nonchlorinated hydrocarbon solvents were not clearly associated with scleroderma.

Systemic sclerosis (SSc) is a multisystem disease of presumed autoimmune pathogenesis for which no proven effective treatment exists. High-dose immunosuppressive therapy (HDIT) has been proposed as an investigational treatment for severe autoimmune diseases. Nineteen patients with poor-prognosis SSc underwent HDIT. The median age was 40 years (range, 23-61 years), the median modified Rodnan skin score (a measure of dermal sclerosis) was 31, and the median DLCO was 57%. Conditioning therapy involved 800 cGy total body irradiation (TBI) (± lung shielding to approximately 200 cGy), 120 mg/kg cyclophosphamide, and 90 mg/kg equine antithymocyte globulin. CD34-selected granulocyte–colony-stimulating factor–mobilized autologous blood stem cells provided hematopoietic rescue. With median follow-up at 14.7 months, the Kaplan-Meier estimated 2-year survival rate was 79%. Three patients died of treatment complications and one of disease progression. Two of the first 8 patients had fatal regimen-related pulmonary injury, a complication not found among 11 subsequent patients who received lung shielding for TBI. Overall, internal organ functions were stable to slightly worse after HDIT, and 4 patients had progressive or nonresponsive disease. As measured by modified Rodnan skin scores and modified health assessment questionnaire disability index (mHAQ-DI) scores, significant disease responses occurred in 12 of 12 patients evaluated at 1 year after HDIT. In conclusion, though important treatment-related toxicities occurred after HDIT for SSc, modifications of initial approaches appear to reduce treatment risks. Responses in skin and mHAQ-DI scores exceed those reported with other therapies, suggesting that HDIT is a promising new therapy for SSc that should be evaluated in prospective randomized studies.

Scleroderma (Systemic Sclerosis, SSc) is a chronic, incurable autoimmune disease associated with high morbidity and mortality primarily due to lung disease. There is a large variability in individual patients courses and current predictors of disease progression are inadequate. The overall objective of the proposed research is to develop reliable predictors for clinical outcomes in scleroderma, utilizing the biospecimens and longitudinal clinical data in the GENISOS cohort combining data from multiple areas to develop robust prediction models for ILD progression. The GENISOS cohort is a unique and valuable resource for biomarker development; no other early SSc cohort exists that has serial biological samples linked to longitudinal clinical data and genetic markers. GENISOS is an inception cohort that avoids survival bias inherent in studies of prevalent cases (mean disease duration at GENISOS entry = 2.5 years, eligibility criterion mandates disease duration 5 years). The cohort was originally established in 1998 and this funding support permitted us to enroll additional patients, continue follow-upon previously enrolled subjects, collect bio-specimens (DNA, RNA in PAX gene tubes, serum, plasma, skin biopsies), perform laboratory studies and analysis as detailed in the Overall Project Summary section of the final report.

There has been a substantial increase in the number of successful African Americans. However, many students, especially African American males, continue to encounter numerous academic obstacles. This chapter focuses on the factors (e.g., social, academic, personal, and familial) that African American males often have to navigate throughout their PreK-12 schooling. Hindrances, such as poverty, lack of academic readiness, poor school experiences, teacher quality, and peer influences, often negatively impact the academic progress of these students and their access to higher level or gifted instruction. In this chapter, the authors discuss strategies that best counter these factors and support and supplement gifted black boys’ educational experiences. Additionally, educational practice and policy recommendations are provided.

Objective. Dyspnoea is a common, multifactorial source of functional impairment among patients with dcSSc. Our objective was to assess the reliability, construct validity and responsiveness to change of the Saint George’s Respiratory Questionnaire (SGRQ) in patients with early dcSSc participating in a multicentre prospective study. Methods. At enrolment and 1 year, patients completed the SGRQ (a multi-item instrument with four scales: symptoms, activity, impact and total), a visual analogue scale (VAS) for breathing and the HAQ Disability Index (HAQ-DI) and underwent 6 min walk distance and pulmonary function tests, physician and patient global health assessments and high-resolution CT (HRCT). We assessed internal consistency reliability using Cronbach’s α. For validity we examined the ability of the SGRQ to differentiate the presence vs absence of interstitial lung disease (ILD) on HRCT or restrictive lung disease and evaluated the 1 year responsiveness to change using pulmonary function tests and patient- and physician-reported anchors. Correlation coefficients of 0.24–0.36 were considered moderate and >0.37 was considered large. Results. A total of 177 patients were evaluated. Reliability was satisfactory for all SGRQ scales (0.70–0.93). All scales showed large correlations with the VAS for breathing and diffusing capacity of the lung for carbon monoxide in the overall cohort and in the subgroup with ILD. Three of the four scales in the overall cohort and the total scale in the ILD subgroup showed moderate to large correlation with the HAQ-DI and the predicted forced vital capacity (r = 0.33–0.44). Each scale discriminated between the presence and absence of ILD and restrictive lung disease (P ≤ 0.0001–0.03). At follow-up, all scales were responsive to change using different anchors. Conclusion. The SGRQ has acceptable reliability, construct validity and responsiveness to change for use in a dcSSc population and differentiates between patients with and without ILD.

Contains fulltext : 136617.pdf (Publisher’s version ) (Open Access) BACKGROUND: Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon. METHODS: We isolated plasmacytoid dendritic cells from healthy persons and from patients with systemic sclerosis who had distinct clinical phenotypes. We then performed proteome-wide analysis and validated these observations in five large cohorts of patients with systemic sclerosis. Next, we compared the results with those in patients with systemic lupus erythematosus, ankylosing spondylitis, and hepatic fibrosis. We correlated plasma levels of CXCL4 protein with features of systemic sclerosis and studied the direct effects of CXCL4 in vitro and in vivo. RESULTS: Proteome-wide analysis and validation showed that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in circulation and in skin. The mean (+/-SD) level of CXCL4 in patients with systemic sclerosis was 25,624+/-2652 pg per milliliter, which was significantly higher than the level in controls (92.5+/-77.9 pg per milliliter) and than the level in patients with systemic lupus erythematosus (1346+/-1011 pg per milliliter), ankylosing spondylitis (1368+/-1162 pg per milliliter), or liver fibrosis (1668+/-1263 pg per milliliter). CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro, CXCL4 down-regulated expression of transcription factor FLI1, induced markers of endothelial-cell activation, and potentiated responses of toll-like receptors. In vivo, CXCL4 induced the influx of inflammatory cells and skin transcriptome changes, as in systemic sclerosis. CONCLUSIONS: Levels of CXCL4 were elevated in patients with systemic sclerosis and correlated with the presence and progression of complications, such as lung fibrosis and pulmonary arterial hypertension. (Funded by the Dutch Arthritis Association and others.).

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.

The fifth author, Brock E. Harper, was incorrectly indicated as having contributed equally to the paper with the first and second authors.

Clinically, systemic sclerosis is dominated by two features: small vessel vasculopathy and organ fibrosis. These two pathological features are responsible for the clinical manifestations of Raynaud’s phenomenon, digital ulcers, renal crisis, pulmonary arterial hypertension, skin thickening, interstitial lung disease, cardiac complications, and other organ involvement. In spite of this commonality, there is a great deal of heterogeneity in disease expression in scleroderma with some individuals having mild involvement and others with severe and progressive disease.

Calcinosis cutis is defined as deposition of insoluble calcium salts in the skin and subcutaneous tissues. It can occur in multiple disorders but it is commonly seen in systemic sclerosis (SSc) especially in the limited type. It is frequently a late finding, but can develop at any point during the disease process and the severity varies from single small lesions typically in the hands to generalized calcinosis also known as calcinosis universalis. The pathogenesis is not well understood but theories include calcium and phosphate microenvironment imbalance, inflammatory causes, and chronic/recurrent ischemia. Calcinosis cutis is a common cause of morbidity in SSc patients and currently there is no treatment consensus although multiple therapies have been attempted with varying degrees of success.

Scleroderma-like or pseudo-scleroderma disorders are a wide group of diseases with various etiologies that lead to skin fibrosis therefore mimicking systemic sclerosis. Although they all have skin thickening in common, the distribution, pattern, and character of the involvement as well as systemic manifestations vary between them. The importance of recognizing these mimics resides in their different prognoses and treatment options. A complete clinical history, detailed physical exam as well as laboratory studies and skin biopsy can help differentiate them.