Scleroderma Renal Crisis: A Pathology Perspective

Scleroderma renal crisis (SRC) is an infrequent but serious complication of systemic sclerosis (SSc). It is associated with increased vascular permeability, activation of coagulation cascade, and renin secretion, which may lead to the acute renal failure typically associated with accelerated hypertension. The histologic picture of SRC is that of a thrombotic microangiopathy process with prominent small vessel involvement manifesting as myxoid intimal changes, thrombi, onion skin lesions, and/or fibrointimal sclerosis. Renal biopsies play an important role in confirming the clinical diagnosis, excluding overlapping/superimposed diseases that might lead to acute renal failure in SSc patients, helping to predict the clinical outcome and optimizing patient management. Kidney transplantation may be the only treatment option available for a subset of SRC patients who develop end-stage renal failure despite aggressive angiotensin-converting enzyme inhibitor therapy. However, the posttransplant outcome for SSc patients is currently suboptimal compared to the general renal transplant population

Clinical and serological features of systemic sclerosis in a multicenter African American cohort: Analysis of the genome research in African American scleroderma patients clinical database.

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

Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis

BACKGROUND: Systemic sclerosis is a disease of unknown origin which often occurs in women after their childbearing years. It has many clinical and histopathological similarities to chronic graft-versus-host disease. Recent studies indicate that fetal stem cells can survive in the maternal circulation for many years post partum. This finding suggests that fetal cells persisting in the maternal circulation or tissues could be involved in the pathogenesis of systemic sclerosis by initiating a graft-versus-host reaction. METHODS: We used the polymerase chain reaction (PCR) to identify Y-chromosome sequences in DNA extracted from peripheral-blood cells and skin lesions from women with systemic sclerosis of recent onset. To confirm the PCR findings, we used fluorescence in situ hybridization of peripheral-blood cells and cells within chronic inflammatory-cell infiltrates in biopsy specimens of affected skin. RESULTS: Y-chromosome sequences were found in DNA from peripheral-blood cells in 32 of 69 women with systemic sclerosis (46 percent), as compared with 1 of 25 normal women (4 percent, P\u3c0.001), and in T lymphocytes from 3 women with systemic sclerosis who had male offspring. Furthermore, Y-chromosome sequences were identified in skin-biopsy specimens from 11 of 19 women with systemic sclerosis (58 percent); 9 of the 11 were known to have carried male fetuses. Nucleated cells containing Y chromosomes were detected by fluorescence in situ hybridization in paraffin-embedded sections of skin lesions from all seven women we tested whose skin-biopsy specimens contained Y-chromosome sequences. CONCLUSIONS: Fetal antimaternal graft-versus-host reactions may be involved in the pathogenesis of systemic sclerosis in some women

<i>HLA</i> and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry

Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1*08:04 and HLA-DRB1*11:02 alleles were associated with overall SSc risk, and the HLA-DRB1*08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1*13:01 and HLA-DRB1*07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1*13:01 allele with the ATA+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1*13:01 allele frequency in multiple populations was observed (r = 0.98, P = 3 × 10−6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA &#x3B1; / &#x3B2; allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc

Survival and Predictors of Mortality in Systemic Sclerosis‐Associated Pulmonary Arterial Hypertension: Outcomes From the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Registry

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106105/1/acr22121.pd

Serum Neurotrophin Profile in Systemic Sclerosis

International audienceBACKGROUND: Neurotrophins (NTs) are able to activate lymphocytes and fibroblasts; they can modulate angiogenesis and sympathic vascular function. Thus, they can be implicated in the three pathogenic processes of systemic sclerosis (SSc). The aims of this study are to determine blood levels of Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF) and Neurotrophin-3 (NT-3) in SSc and to correlate them with clinical and biological data.METHODS: Serum samples were obtained from 55 SSc patients and 32 control subjects to measure NTs levels by ELISA and to determine their relationships with SSc profiles. FINDINGS: Serum NGF levels were higher in SSc patients (288.26 ± 170.34 pg/mL) than in control subjects (170.34 ± 50.8 pg/mL, p<0.001) and correlated with gammaglobulins levels and the presence of both anti-cardiolipin and anti-Scl-70 antibodies (p<0.05). In contrast, BDNF levels were lower in SSc patients than in controls (1121.9 ± 158.1 vs 1372.9 ± 190.9 pg/mL, p<0.0001), especially in pulmonary arterial hypertension and diffuse SSc as compared to limited forms (all p<0.05). NT-3 levels were similar in SSc and in the control group (2657.2 ± 2296 vs 2959.3 ± 2555 pg/mL, NS). BDNF levels correlated negatively with increased NGF levels in the SSc group (and not in controls). CONCLUSION: Low BDNF serum levels were not previously documented in SSc, particularly in the diffuse SSc subset and in patients with pulmonary hypertension or anti-Scl-70 antibodies. The negative correlation between NGF and BDNF levels observed in SSc and not in healthy controls could be implicated in sympathic vascular dysfunction in SSc

β-thymosins and interstitial lung disease: study of a scleroderma cohort with a one-year follow-up

Background: beta-thymosins play roles in cytoskeleton rearrangement, angiogenesis, fibrosis and reparative process, thus suggesting a possible involvement in the pathogenesis of systemic sclerosis. The aim of the study was to investigate the presence of thymosins beta(4), beta(4) sulfoxide, and beta(10) in bronchoalveolar lavage fluid of scleroderma patients with interstitial lung disease and the relation of these factors with pulmonary functional and radiological parameters. Methods: beta-thymosins concentrations were determined by Reverse Phase-High Performance Liquid Chromatography-Electrospray-Mass Spectrometry in the bronchoalveolar lavage fluid of 46 scleroderma patients with lung involvement and of 15 controls. Results: Thymosin beta(4), beta(4) sulfoxide, and beta(10) were detectable in bronchoalveolar lavage fluid of patients and controls. Thymosin beta(4) levels were significantly higher in scleroderma patients than in controls. In addition, analyzing the progression of scleroderma lung disease at one-year follow-up, we have found that higher thymosin beta(4) levels seem to have a protective role against lung tissue damage. Thymosin beta(4) sulfoxide levels were higher in the smokers and in the scleroderma patients with alveolitis. Conclusions: We describe for the first time beta-thymosins in bronchoalveolar lavage fluid and their possible involvement in the pathogenesis of scleroderma lung disease. Thymosin beta(4) seems to have a protective role against lung tissue damage, while its oxidation product mirrors an alveolar inflammatory statu

Oral health of Chinese people with systemic sclerosis

The aim was to study oral health status, salivary function, and oral features of Chinese people with Systemic Sclerosis (SSc). Chinese people with SSc attending a university specialist clinic were invited for a questionnaire survey and a clinical examination. Ethics approval was sought (UW 08-305). Gender- and age-matched individuals without SSc who attended a university dental hospital were recruited for comparison. Forty-two SSc patients with a mean age of 54.0 ± 12.2 were examined. This study found no Chinese people with systemic sclerosis were periodontally healthy and many (76%) had periodontal pockets despite most of them (93%) practiced daily tooth-brushing. They all had caries experience (DMFT = 10.5) and many (65%) had untreated decay. Mucosal telangiectasia was a common oral feature (80%). They had lower resting salivary flow rates (0.18 ± 0.17 ml/min vs. 0.31 ± 0.21 ml/min; p = 0.003) and pH values (6.90 ± 0.40 vs. 7.28 ± 0.31; p < 0.001) and reduced maximal mouth opening (40.1 ± 6.5 mm vs. 43.6 ± 7.0 mm) than people without SSc

The 'new majority' and the academization of journalism

The academization of journalism is reliant on the development of the field founded in scholarship demonstrated through the publication of research in peer-reviewed specialist journals. Given the profile of journalism faculty, this means inducting practitioners into a culture of critical research. In Australia at least, this cohort of neophytes is predominantly comprised of middle-aged women who were surveyed about their personal attitudes to research. They were mostly open to the idea of becoming researchers but were inclined to proceed cautiously without necessarily severing their ties with practice. There was evidence to suggest that a generally positive orientation to research was not capitalized on and that they remained uncertain about the role of research. On the other hand, they appeared not to have adopted the orthodoxy of implacable opposition to scholarly inquiry. The change in gender composition in the academy may provide, contrary to historical, but more in line with contemporary, evidence, a renewed impetus to the project of academizing the field