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1.  Influence of prior pregnancies on disease course and cause of death in systemic sclerosis 
Annals of the Rheumatic Diseases  2002;61(4):346-350.
Background: Microchimerism from fetal or maternal cells transferred during pregnancy has been implicated in the pathogenesis of systemic sclerosis (SSc).
Objective: To determine whether a prior pregnancy influenced disease progression and cause of death in patients with SSc.
Patients and methods: The patients comprised a retrospective study cohort of 111 women with SSc: 78 patients with prior pregnancies (PP) and 33 who were never pregnant (NP), followed up at Thomas Jefferson University. Differences in age at onset, disease subset, organ involvement, cause of death, and type of antinuclear autoantibodies were evaluated statistically, including regression analysis.
Results: The age at onset of SSc in NP patients was 32.0 years compared with 45.7 years in patients with one or two prior pregnancies (p<0.0001), 46.6 years in patients with three or four pregnancies (p<0.0001), and 51.3 years in patients with five to seven pregnancies (p<0.0005). In the 16 patients who had an elective pregnancy termination, 14/16 (87.5%) had diffuse SSc v 2/16 (12.5%) with limited SSc (p<0.0001; odds ratio (OR)=49.0). Of the NP women, 7/30 (23%) died from SSc related causes v 3/78 (4%) women who had pregnancies (p=0.0058; OR=7.6). A carbon monoxide transfer factor (TLCO) of <60% and disease duration >10 years was found in 10/13 (77%) NP patients v 10/23 (43%) patients who had pregnancies (p=0.05; OR=4.7), and a TLCO <50% and disease duration >10 years was identified in 7/13 (54%) NP patients v 6/23 (26%) of the patients who had pregnancies (p=0.09; OR=3.2).
Conclusions: There are differences in the age at onset, clinical course, severity of lung involvement, and cause of death in women who develop SSc before pregnancy compared with those who develop it after pregnancies. The NP patients with SSc had onset of disease at an earlier age, more severe lung involvement, and higher rate of death due to SSc.
PMCID: PMC1754050  PMID: 11874839
2.  Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry 
Annals of the Rheumatic Diseases  2012;71(5):718-721.
The Digital Ulcers Outcome (DUO) Registry was designed to describe the clinical and antibody characteristics, disease course and outcomes of patients with digital ulcers associated with systemic sclerosis (SSc).
The DUO Registry is a European, prospective, multicentre, observational, registry of SSc patients with ongoing digital ulcer disease, irrespective of treatment regimen. Data collected included demographics, SSc duration, SSc subset, internal organ manifestations, autoantibodies, previous and ongoing interventions and complications related to digital ulcers.
Up to 19 November 2010 a total of 2439 patients had enrolled into the registry. Most were classified as either limited cutaneous SSc (lcSSc; 52.2%) or diffuse cutaneous SSc (dcSSc; 36.9%). Digital ulcers developed earlier in patients with dcSSc compared with lcSSc. Almost all patients (95.7%) tested positive for antinuclear antibodies, 45.2% for anti-scleroderma-70 and 43.6% for anticentromere antibodies (ACA). The first digital ulcer in the anti-scleroderma-70-positive patient cohort occurred approximately 5 years earlier than the ACA-positive patient group.
This study provides data from a large cohort of SSc patients with a history of digital ulcers. The early occurrence and high frequency of digital ulcer complications are especially seen in patients with dcSSc and/or anti-scleroderma-70 antibodies.
PMCID: PMC3329234  PMID: 22247218
3.  Histopathological cutaneous alterations in systemic sclerosis: a clinicopathological study 
The aims of the present study were to identify histopathological parameters which are linked to local clinical skin disease at two distinct anatomical sites in systemic sclerosis (SSc) patients with skin involvement (limited cutaneous systemic sclerosis (lcSSc) or diffuse cutaneous systemic sclerosis (dcSSc)) and to determine the sensitivity of SSc specific histological alterations, focusing on SSc patients without clinical skin involvement (limited SSc (lSSc)).
Histopathological alterations were systematically scored in skin biopsies of 53 consecutive SSc patients (dorsal forearm and upper inner arm) and 18 controls (upper inner arm). Clinical skin involvement was evaluated using the modified Rodnan skin score. In patients with lcSSc or dcSSc, associations of histopathological parameters with local clinical skin involvement were determined by generalised estimation equation modelling.
The hyalinised collagen score, the myofibroblast score, the mean epidermal thickness, the mononuclear cellular infiltration and the frequency of focal exocytosis differed significantly between biopsies with and without local clinical skin involvement. Except for mononuclear cellular infiltration, all of the continuous parameters correlated with the local clinical skin score at the dorsal forearm. Parakeratosis, myofibroblasts and intima proliferation were present in a minority of the SSc biopsies, but not in controls. No differences were found between lSSc and controls.
Several histopathological parameters are linked to local clinical skin disease. SSc-specific histological alterations have a low diagnostic sensitivity.
PMCID: PMC3241379  PMID: 21356083
4.  Vascular Complications of Systemic Sclerosis during Pregnancy 
Systemic sclerosis (SSc) is a chronic autoimmune disorder characterized by progressive fibrosis of the skin and visceral tissues as well as a noninflammatory vasculopathy. Vascular disease in systemic sclerosis is a major cause of morbidity and mortality among nonpregnant patients with SSc and is even a bigger concern in the pregnant SSc patient, as the underlying vasculopathy may prevent the required hemodynamic changes necessary to support a growing pregnancy. Vascular manifestations including scleroderma renal crisis and pulmonary arterial hypertension should be considered relative contraindications against pregnancy due to the high associations of both maternal and fetal morbidity and mortality. In contrast, Raynaud's phenomenon may actually improve somewhat during pregnancy. Women with SSc who are considering a pregnancy or discover they are pregnant require evaluation for the presence and extent of underlying vasculopathy. In the absence of significant visceral vasculopathy, most women with SSc can expect to have reasonable pregnancy outcomes.
PMCID: PMC2931377  PMID: 20814538
5.  Pregnancy and the risk of autoimmune disease 
Chimerism  2011;2(3):84-85.
Fetal microchimerism is the study of persisting fetal cells in the mother years after pregnancy and the purported implications for her health and longevity. Due to the association between pregnancy and autoimmune disease (AID), and the preponderance of these diseases in women, laboratory studies have for years attempted to link microchimeric fetal cells with the onset of AID after pregnancy. This new study gave us the opportunity to examine for the first time if this theory could be proven clinically in a large cohort of women. By examining whether different types of delivery affected the onset of AID, we also aimed to indirectly relate this finding to fetal microchimerism. The results did suggest an association between pregnancy and the risk of subsequent maternal AID, with increased risks noted after caesarean section (CS) and decreased risks after abortion. This is the first epidemiological study on the risk of AID following pregnancy.
PMCID: PMC3234360  PMID: 22163066
pregnancy; autoimmune disease; fetal cells; microchimerism; caesarean section; abortion
6.  Fetal microchimeric cells in autoimmune thyroid diseases 
Chimerism  2013;4(4):111-118.
Autoimmune thyroid diseases (AITD) show a female predominance, with an increased incidence in the years following parturition. Fetal microchimerism has been suggested to play a role in the pathogenesis of AITD. However, only the presence of fetal microchimeric cells in blood and in the thyroid gland of these patients has been proven, but not an actual active role in AITD. Is fetal microchimerism harmful for the thyroid gland by initiating a Graft versus Host reaction (GvHR) or being the target of a Host versus Graft reaction (HvGR)? Is fetal microchimerism beneficial for the thyroid gland by being a part of tissue repair or are fetal cells just innocent bystanders in the process of autoimmunity? This review explores every hypothesis concerning the role of fetal microchimerism in AITD.
PMCID: PMC3921191  PMID: 23723083
Graft-vs.-Host reaction; Graves disease; HLA-compatibility; Hashimoto’s Thyroiditis; autoimmune thyroid disease; fetal microchimerism
Immunological investigations  2008;37(5):631-644.
Pregnancy has both short-term effects and long-term consequences. For women who have an autoimmune disease and subsequently become pregnant, pregnancy can induce amelioration of the mother’s disease, such as in rheumatoid arthritis, while exacerbating or having no effect on other autoimmune diseases like systemic lupus erythematosus. That pregnancy also leaves a long-term legacy has recently become apparent by the discovery that bi-directional cell trafficking results in persistence of fetal cells in the mother and of maternal cells in her offspring for decades after birth. The long-term persistence of a small number of cells (or DNA) from a genetically disparate individual is referred to as microchimerism. While microchimerism is common in healthy individuals and is likely to have health benefits, microchimerism has been implicated in some autoimmune diseases such as systemic sclerosis. In this paper, we will first discuss short-term effects of pregnancy on women with autoimmune disease. Pregnancy-associated changes will be reviewed for selected autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus and autoimmune thyroid disease. The pregnancy-induced amelioration of rheumatoid arthritis presents a window of opportunity for insights into both immunological mechanisms of fetal-maternal tolerance and pathogenic mechanisms in autoimmunity. A mechanistic hypothesis for the pregnancy-induced amelioration of rheumatoid arthritis will be described. We will then discuss the legacy of maternal-fetal cell transfer from the perspective of autoimmune diseases. Fetal and maternal microchimerism will be reviewed with a focus on systemic sclerosis (scleroderma), autoimmune thyroid disease, neonatal lupus and type I diabetes mellitus.
PMCID: PMC2709983  PMID: 18716941
autoimmune disease; pregnancy; microchimerism; systemic lupus erythematosus; rheumatoid arthritis
8.  A Research Study of the Association between Maternal Microchimerism and Systemic Lupus Erythematosus in Adults: A Comparison between Patients and Healthy Controls Based on Single-Nucleotide Polymorphism Using Quantitative Real-Time PCR 
PLoS ONE  2013;8(9):e74534.
Naturally acquired microchimerism may arise in the mother and her child during pregnancy when bidirectional trafficking of cells occurs through the placental barrier. The occurrence of maternal microchimerism (maternal cells in the offspring) has been associated with several autoimmune diseases, especially in children. Systemic Lupus erythematosus (SLE) is an autoimmune disorder with a resemblance to graft-versus-host disease. The aim of this study was to investigate the association between maternal microchimerism in the blood and SLE.
Methodology/Principal Findings
Thirty-two patients with SLE, 17 healthy brothers of the patients, and an additional 12 unrelated healthy men were the subjects in this study. A single-nucleotide polymorphism unique to each mother was identified, and maternal microchimerism in the study group and in the control group was detected using a quantitative real-time polymerase chain reaction technique. No differences in the frequency or the concentration of maternal cells were apparent in the blood of patients with SLE or in that of the controls. Two patients and one control tested positive for maternal microchimerism, but the positive subjects were all negative at a follow-up 16 years later. The sensitivity of the method was estimated to 1/10.000.
These results show no association between SLE and maternal microchimerism. The frequency of maternal microchimerism in the blood of adults overall may be lower than earlier reported.
PMCID: PMC3770650  PMID: 24040274
9.  Allogeneic Marrow Transplantation in Patients With Severe Systemic Sclerosis 
Arthritis and rheumatism  2006;54(6):1982-1986.
To evaluate the safety and efficacy of allogeneic hematopoietic cell transplantation (HCT) after myeloablative conditioning in patients with severe systemic sclerosis (SSc).
Eligibility criteria for the study included SSc patients with features indicative of a poor prognosis. The myeloablative conditioning regimen included busulfan, cyclophosphamide, and antithymocyte globulin. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporine and methotrexate. Bone marrow was transplanted from HLA-identical siblings.
Two patients with diffuse cutaneous SSc and lung involvement who were refractory to conventional immunosuppressive treatment were enrolled in the study. In patient 1, there were no complications related to the conditioning regimen, and GVHD did not develop after transplantation. At 5 years after HCT, there was nearly complete resolution of the scleroderma and marked improvement in physical functioning. Internal organ function improved (lung) or remained stable. On examination of serial skin biopsy samples, there was resolution of the dermal fibrosis. Patient 2 experienced skin toxicity from the conditioning regimen and hypertensive crisis that was likely related to high-dose corticosteroids given for treatment of GVHD. Although this patient experienced an improvement in scleroderma and overall functioning, a fatal opportunistic infection developed 17 months after HCT.
Allogeneic HCT may result in sustained remission of SSc. GVHD and opportunistic infections are the major risks associated with allogeneic HCT for SSc, as for allogeneic HCT in general.
PMCID: PMC2956579  PMID: 16732546
10.  Naturally acquired microchimerism 
Bi-directional transplacental trafficking occurs routinely during the course of normal pregnancy, from fetus to mother and from mother to fetus. In addition to a variety of cell-free substances, it is now well recognized that some cells are also exchanged. Microchimerism refers to a small number of cells (or DNA) harbored by one individual that originated in a genetically different individual. While microchimerism can be the result of iatrogenic interventions such as transplantation or transfusion, by far the most common source is naturally acquired microchimerism from maternal-fetal trafficking during pregnancy. Microchimerism is a subject of much current interest for a number of reasons. During pregnancy, fetal microchimerism can be sought from the mother’s blood for the purpose of prenatal diagnosis. Moreover, studies of fetal microchimerism during pregnancy may offer insight into complications of pregnancy, such as preeclampsia, as well as insights into the pathogenesis of autoimmune diseases such as rheumatoid arthritis which usually ameliorates during pregnancy. Furthermore, it is now known that microchimerism persists decades later, both fetal microchimerism in women who have been pregnant and maternal microchimerism in her progeny. Investigation of the long-term consequences of fetal and maternal microchimerism is another exciting frontier of active study, with initial results pointing both to adverse and beneficial effects. This review will provide an overview of microchimerism during pregnancy and of current knowledge regarding long-term effects of naturally acquired fetal and maternal microchimerism.
PMCID: PMC2887685  PMID: 19924635
microchimerism; pregnancy; fetal-maternal trafficking; autoimmune disease
11.  A Mouse Model for Fetal Maternal Stem Cell Transfer During Ischemic Cardiac Injury 
Fetal cells enter the maternal circulation during pregnancies and can persist in blood and tissues for decades, creating a state of physiologic microchimerism. Microchimerism refers to acquisition of cells from another individual and can be due to bi-directional cell traffic between mother and fetus during pregnancy. Peripartum cardiomyopathy, a rare cardiac disorder associated with high mortality rates has the highest recovery rate amongst all etiologies of heart failure although the reason is unknown. Collectively, these observations led us to hypothesize that fetal cells enter the maternal circulation and may be recruited to the sites of myocardial disease or injury. The ability to genetically modify mice makes them an ideal system for studying the phenomenon of microchimerism in cardiac disease. Described here is a mouse model for ischemic cardiac injury during pregnancy designed to study microchimerism. Wild-type virgin female mice mated with eGFP male mice underwent ligation of the left anterior descending artery to induce a myocardial infarction at gestation day 12. We demonstrate the selective homing of eGFP cells to the site of cardiac injury without such homing to nonfinjured tissues suggesting the presence of precise signals sensed by fetal cells enabling them to target diseased myocardium specifically.
PMCID: PMC3419501  PMID: 22883609
12.  Work Disability in Scleroderma is Greater than in Rheumatoid Arthritis and is Predicted by High HAQ Scores 
To estimate the frequency of work disability (WD) in a cohort of patients with Systemic Sclerosis (SSc) vs an internal control group of patients with rheumatoid arthritis (RA) with a known high frequency of WD; and to investigate the association between WD and other factors including Health Assessment Questionnaire Disability Index (HAQ-DI) scores, HAQ pain, age, sex, disease duration and education level.
Cross-sectional data on WD status were obtained from a questionnaire sent to all SSc (n = 35 limited [lcSSc], 26 diffuse [dcSSc]) and a subset of RA patients (n=104) from a rheumatology practice. WD data, HAQ-DI scores, and demographic/clinical features (age, sex, high school education, disease duration and SSc disease subtype [dcSSc vs lcSSc]) were recorded.
The proportion with WD was 0.56 in SSc (95% CI: 0.43-0.68) vs 0.35 in RA (95% CI: 0.25-0.44), p= 0.009. HAQ-DI scores were significantly higher in work-disabled SSc and RA patients vs those who were employed (p=0.0001, and p <0.0001). Multivariate logistic regression analysis demonstrated that higher HAQ-DI scores (β=1.78, p <0.001), disease type (dcSSc, lcSSc, RA) (β=1.32 for dcSSc, p=0.032), and self-reported disease duration (β=0.04, p=0.042) were significantly associated with WD (R2=0.311). Adding a work-related factor (self-reported physically demanding work) improved the regression model (R2=0.346) and strengthened the HAQ-DI (β=1.86, p <0.001) and lcSSc (β=1.24, p=0.024) coefficients.
The frequency of WD in SSc was high and was greater than in RA. SSc (and dcSSc) had significantly more WD than RA. The HAQ-DI was strongly associated with WD in SSc
PMCID: PMC2588092  PMID: 19088871
Scleroderma; systemic sclerosis; work disability; health assessment questionnaire
13.  Association of Gender with Clinical Expression, Quality of Life, Disability, and Depression and Anxiety in Patients with Systemic Sclerosis 
PLoS ONE  2011;6(3):e17551.
To assess the association of gender with clinical expression, health-related quality of life (HRQoL), disability, and self-reported symptoms of depression and anxiety in patients with systemic sclerosis (SSc).
SSc patients fulfilling the American College of Rheumatology and/or the Leroy and Medsger criteria were assessed for clinical symptoms, disability, HRQoL, self-reported symptoms of depression and anxiety by specific measurement scales.
Overall, 381 SSc patients (62 males) were included. Mean age and disease duration at the time of evaluation were 55.9 (13.3) and 9.5 (7.8) years, respectively. One-hundred-and-forty-nine (40.4%) patients had diffuse cutaneous SSc (dcSSc). On bivariate analysis, differences were observed between males and females for clinical symptoms and self-reported symptoms of depression and anxiety, however without reaching statistical significance. Indeed, a trend was found for higher body mass index (BMI) (25.0 [4.1] vs 23.0 [4.5], p = 0.013), more frequent dcSSc, echocardiography systolic pulmonary artery pressure >35 mmHg and interstitial lung disease in males than females (54.8% vs 37.2%, p = 0.010; 24.2% vs 10.5%, p = 0.003; and 54.8% vs 41.2%, p = 0.048, respectively), whereas calcinosis and self-reported anxiety symptoms tended to be more frequent in females than males (36.0% vs 21.4%, p = 0.036, and 62.3% vs 43.5%, p = 0.006, respectively). On multivariate analysis, BMI, echocardiography PAP>35 mmHg, and anxiety were the variables most closely associated with gender.
In SSc patients, male gender tends to be associated with diffuse disease and female gender with calcinosis and self-reported symptoms of anxiety. Disease-associated disability and HRQoL were similar in both groups.
PMCID: PMC3052319  PMID: 21408076
14.  The Pronounced Th17 Profile in Systemic Sclerosis (SSc) Together with Intracellular Expression of TGFβ and IFNγ Distinguishes SSc Phenotypes 
PLoS ONE  2009;4(6):e5903.
Systemic sclerosis (SSc) is an autoimmune disease where controversy on Th1/Th2 balance dominates. We investigated whether the recently discovered Th17 pattern was present in SSc.
Methodology and Principal Findings
Patients were subdivided as having limited cutaneous SSc (lcSSc, n = 12) or diffuse cutaneous SSc (dcSSc, n = 24). A further arbitrary subdivision was made between early dcSSc (n = 11) and late dcSSc (n = 13) based upon the duration of disease. As a comparator group 14 healthy controls were studied. CD3+ cells were isolated using FACS and subsequently studied for the expression of CD4, CD8, CD25, CD45Ro, CD45Ra, IL-23, GITR, CD69 and intracellular expression of IL-17, TGFβ and IFNγ using flow cytometry. Levels of IL-17, IL-6, IL-1α and IL-23 were measured using Bioplex assays. SSc patients had more and more activated CD4+ cells. In addition, CD4, CD45Ro and CD45Ra cells from all SSc patients highly expressed the IL23R, which was associated with a higher IL-17 expression as well. In contrast, IFNγ and TGFβ were selectively up regulated in SSc subsets. In line with these observation, circulating levels of IL-17 inducing cytokines IL-6, IL-23 and IL-1α were increased in all or subsets of SSc patients.
Conclusion and Significance
The combination of IL-17, IFNγ and TGFβ levels in CD45Ro and CD45Ra cells from SSc patients is useful to distinguish between lSSc, ldSSc or edSSc. Blocking Th17 inducing cytokines such as IL-6 and IL-23 may provide a useful tool to intervene in the progression of SSc.
PMCID: PMC2691991  PMID: 19536281
15.  Systemic sclerosis and the heart: current diagnosis and management 
Current opinion in rheumatology  2011;23(6):545-554.
Purpose of review
When present clinically, cardiac involvement in systemic sclerosis (SSc) is a major risk factor for death. It is therefore vitally important to understand the epidemiology, screening, diagnosis, and treatment of the cardiac manifestations of SSc.
Recent findings
The epidemiology of cardiac involvement in SSc has been the subject of several recent studies. Most importantly, the prevalence of overt left ventricular (LV) systolic dysfunction and its associated risk factors have been defined, and patients with diffuse cutaneous SSc appear to be most susceptible to direct cardiac involvement. From a diagnostic and screening standpoint, tissue Doppler echocardiography and natriuretic peptides have provided fresh insight into subclinical cardiac dysfunction in SSc. Newer techniques, such as speckle-tracking echocardiography, diffuse myocardial fibrosis imaging, and absolute myocardial perfusion imaging, are poised to further advance our knowledge. Lastly, there is now consistent observational data to suggest a central role for calcium channel blockers in the treatment of microvascular ischemia and prevention of overt LV systolic dysfunction, although randomized controlled trials are lacking.
Recent studies have improved our understanding of cardiac involvement in SSc. Nevertheless, key questions regarding screening, diagnosis, and treatment remain. Novel diagnostic techniques and multicenter studies should yield important new data, which will hopefully ultimately result in improved outcomes.
PMCID: PMC3678364  PMID: 21897256
echocardiography; myocardial fibrosis; myocardial perfusion; natriuretic peptides; systemic sclerosis
16.  Vasculitis in Systemic Sclerosis 
Systemic sclerosis (SSc) is a multiorgan connective tissue disease characterized by autoantibody production and fibroproliferative stenosis of the microvasculature. The vascoluopathy associated with SSc is considered to be noninflammatory, yet frank vasculitis can complicate SSc, posing diagnostic and therapeutic challenges. Here, we have reviewed the literature for reports of small-, medium-, and large-vessel vasculitis occurring in SSc. Amongst 88 reported cases of vasculitis in SSc, patients with ANCA-associated vasculitis appear to present a unique subclass in that they combined typical features of SSc with the renal manifestation of ANCA-associated glomerulonephritis. Other vasculitic syndromes, including large-vessel vasculitis, Behcet's disease, cryoglobulinemia, and polyarteritis nodosa, are rarely encountered in SSc patients. ANCA-associated vasculitis needs to be considered as a differential diagnosis in SSc patients presenting with renal insufficiency, as renal manifestations may result from distinct disease processes and require appropriate diagnostic testing and treatment.
PMCID: PMC2952802  PMID: 20976300
17.  Comparative Proteomic Analysis of Serum from Patients with Systemic Sclerosis and Sclerodermatous GVHD. Evidence of Defective Function of Factor H 
PLoS ONE  2010;5(8):e12162.
Systemic sclerosis (SSc) is an autoimmune disease characterized by immunological and vascular abnormalities. Until now, the cause of SSc remains unclear. Sclerodermatous graft-versus-host disease (ScGVHD) is one of the most severe complications following bone marrow transplantation (BMT) for haematological disorders. Since the first cases, the similarity of ScGVHD to SSc has been reported. However, both diseases could have different etiopathogeneses. The objective of this study was to identify new serum biomarkers involved in SSc and ScGVHD.
Serum was obtained from patients with SSc and ScGVHD, patients without ScGVHD who received BMT for haematological disorders and healthy controls. Bi-dimensional electrophoresis (2D) was carried out to generate maps of serum proteins from patients and controls. The 2D maps underwent image analysis and differently expressed proteins were identified. Immuno-blot analysis and ELISA assay were used to validate the proteomic data. Hemolytic assay with sheep erythrocytes was performed to evaluate the capacity of Factor H (FH) to control complement activation on the cellular surface. FH binding to endothelial cells (ECs) was also analysed in order to assess possible dysfunctions of this protein.
Principal Findings
Fourteen differentially expressed proteins were identified. We detected pneumococcal antibody cross-reacting with double stranded DNA in serum of all bone marrow transplanted patients with ScGVHD. We documented higher levels of FH in serum of SSc and ScGVHD patients compared healthy controls and increased sheep erythrocytes lysis after incubation with serum of diffuse SSc patients. In addition, we observed that FH binding to ECs was reduced when we used serum from these patients.
The comparative proteomic analysis of serum from SSc and ScGVHD patients highlighted proteins involved in either promoting or maintaining an inflammatory state. We also found a defective function of Factor H, possibly associated with ECs damage.
PMCID: PMC2921355  PMID: 20730046
18.  Increased expression of endoplasmic reticulum stress genes in patients with limited cutaneous Systemic Sclerosis and Pulmonary Arterial Hypertension 
Arthritis and rheumatism  2013;65(5):1357-1366.
Pulmonary arterial hypertension (PAH), a common complication of limited cutaneous systemic sclerosis (lcSSc), is associated with alterations of markers of inflammation and vascular damage in peripheral blood mononuclear cells (PBMCs). Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) have been implicated in autoimmune and inflammatory diseases. The goal of this study was to assess whether markers of ER stress/UPR are present in PBMCs from lcSSc-PAH patients.
PBMCs were purified from healthy controls (HC, n=36) and lcSSc patients, with and without PAH (lcSSc-PAH, n=32; lcSSc-NoPAH, n=34). Gene expression in HC PBMCs stimulated with thapsigargin (TG) was analyzed by DNA microarray. Genes were validated by qPCR in HC and lcSSc PBMCs.
Several ER stress/UPR genes, including Immunoglobulin-heavy-chain binding protein (BiP), Activating Transcription Factor-4 and -6 (ATF4 and ATF6) and a spliced form of X-box binding protein (XBP1) were upregulated in lcSSc PBMCs, with the highest levels in patients with PAH. TG upregulated Heat shock proteins (HSP) and Interferon-regulated genes in control PBMCs. Selected HSP genes, particularly DNAJB1, and IFN-related genes were also found at significantly elevated levels in PBMCs from lcSSc patients, while IRF4 was significantly decreased. There was a positive correlation between DNAJB1 and severity of PAH disease (PAP) (r = 0.56, p<0.05) and between ER stress markers and IL-6 levels (r = 0.53, p< 0.0001) in lcSSc PBMCs.
This study demonstrates association between select ER stress/UPR markers and lcSSc-PAH suggesting that ER stress/UPR may contribute to the altered function of circulating immune cells in lcSSc.
PMCID: PMC3636187  PMID: 23400395
19.  Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database 
Annals of the Rheumatic Diseases  2007;66(6):754-763.
Systemic sclerosis (SSc) is a multisystem autoimmune disease, which is classified into a diffuse cutaneous (dcSSc) and a limited cutaneous (lcSSc) subset according to the skin involvement. In order to better understand the vascular, immunological and fibrotic processes of SSc and to guide its treatment, the EULAR Scleroderma Trials And Research (EUSTAR) group was formed in June 2004.
Aims and methods
EUSTAR collects prospectively the Minimal Essential Data Set (MEDS) on all sequential patients fulfilling the American College of Rheumatology diagnostic criteria in participating centres. We aimed to characterise demographic, clinical and laboratory characteristics of disease presentation in SSc and analysed EUSTAR baseline visits.
In April 2006, a total of 3656 patients (1349 with dcSSc and 2101 with lcSSc) were enrolled in 102 centres and 30 countries. 1330 individuals had autoantibodies against Scl70 and 1106 against anticentromere antibodies. 87% of patients were women. On multivariate analysis, scleroderma subsets (dcSSc vs lcSSc), antibody status and age at onset of Raynaud's phenomenon, but not gender, were found to be independently associated with the prevalence of organ manifestations. Autoantibody status in this analysis was more closely associated with clinical manifestations than were SSc subsets.
dcSSc and lcSSc subsets are associated with particular organ manifestations, but in this analysis the clinical distinction seemed to be superseded by an antibody‐based classification in predicting some scleroderma complications. The EUSTAR MEDS database facilitates the analysis of clinical patterns in SSc, and contributes to the standardised assessment and monitoring of SSc internationally.
PMCID: PMC1954657  PMID: 17234652
20.  Cutaneous Chronic Graft-Versus-Host Disease Does Not Have the Abnormal Endothelial Phenotype or Vascular Rarefaction Characteristic of Systemic Sclerosis 
PLoS ONE  2009;4(7):e6203.
The clinical and histologic appearance of fibrosis in cutaneous lesions in chronic graft-versus -host disease (c-GVHD) resembles the appearance of fibrosis in scleroderma (SSc). Recent studies identified distinctive structural changes in the superficial dermal microvasculature and matrix of SSc skin. We compared the dermal microvasculature in human c-GVHD to SSc to determine if c-GVHD is a suitable model for SSc.
Methodology/Principal Findings
We analyzed skin biopsies of normal controls (n = 24), patients with SSc (n = 30) and c-GVHD with dermal fibrosis (n = 133)). Immunostaining was employed to identify vessels, vascular smooth muscle, dermal matrix, and cell proliferation. C-GVHD and SSc had similar dermal matrix composition and vascular smooth muscle pathology, including intimal hyperplasia. SSc, however, differed significantly from c-GVHD in three ways. First, there were significantly fewer (p = 0.00001) average vessels in SSc biopsies (9.8) when compared with c-GVHD (16.5). Second, in SSc, endothelial markers were decreased significantly (19/19 and 12/14 for VE cadherin and vWF (p = <0.0001 and <0.05), respectively). In contrast, 0/13 c-GVHD biopsies showed loss of staining with canonical endothelial markers. Third, c-GVHD contained areas of microvascular endothelial proliferation not present in the SSc biopsies.
The sclerosis associated with c-GVHD appears to resemble wound healing. Focal capillary proliferation occurs in early c-GVHD. In contrast, loss of canonical endothelial markers and dermal capillaries is seen in SSc, but not in c-GVHD. The loss of VE cadherin in SSc, in particular, may be related to microvascular rarefaction because VE cadherin is necessary for angiogenesis. C-GVHD is a suitable model for studying dermal fibrosis but may not be applicable for studying the microvascular alterations characteristic of SSc.
PMCID: PMC2705674  PMID: 19587802
21.  Increased Frequency and Compromised Function of T Regulatory Cells in Systemic Sclerosis (SSc) Is Related to a Diminished CD69 and TGFβ Expression 
PLoS ONE  2009;4(6):e5981.
Regulatory T cells (Tregs) are essential in the control of tolerance. Evidence implicates Tregs in human autoimmune conditions. Here we investigated their role in systemic sclerosis (SSc).
Methods/Principal Findings
Patients were subdivided as having limited cutaneous SSc (lcSSc, n = 20) or diffuse cutaneous SSc (dcSSc, n = 48). Further subdivision was made between early dcSSc (n = 24) and late dcSSc (n = 24) based upon the duration of disease. 26 controls were studied for comparison. CD3+ cells were isolated using FACS and subsequently studied for the expression of CD4, CD8, CD25, FoxP3, CD127, CD62L, GITR, CD69 using flow cytometry. T cell suppression assays were performed using sorted CD4CD25highCD127- and CD4CD25lowCD127high and CD3+ cells. Suppressive function was correlated with CD69 surface expression and TGFβ secretion/expression. The frequency of CD4+CD25+ and CD25highFoxP3highCD127neg T cells was highly increased in all SSc subgroups. Although the expression of CD25 and GITR was comparable between groups, expression of CD62L and CD69 was dramatically lower in SSc patients, which correlated with a diminished suppressive function. Co-incubation of Tregs from healthy donors with plasma from SSc patients fully abrogated suppressive activity. Activation of Tregs from healthy donors or SSc patients with PHA significantly up regulated CD69 expression that could be inhibited by SSc plasma.
These results indicate that soluble factors in SSc plasma inhibit Treg function specifically that is associated with altered Treg CD69 and TGFβ expression. These data suggest that a defective Treg function may underlie the immune dysfunction in systemic sclerosis.
PMCID: PMC2695559  PMID: 19543397
22.  Antigen specificity of antihistone antibodies in systemic sclerosis 
Annals of the Rheumatic Diseases  1998;57(8):470-475.
OBJECTIVES—The aim of the study was to determine the prevalence and clinical significance of antibodies to individual histone components in systemic sclerosis (SSc).
METHODS—Serum samples from patients with limited cutaneous SSc (lSSc; n=42) and diffuse cutaneous SSc (dSSc; n=28) were examined for IgG and/or IgM antibodies to individual histone components and complexes by enzyme linked immunosorbent assay (ELISA).
RESULTS—The level of IgG antibody to total histones was significantly higher in lSSc and dSSc than in normal controls. The level of IgM antibody to total histones was significantly higher in lSSc, but not in dSSc, than in normal controls. IgG antibody to total histones tended to be increased in dSSc when compared with that in lSSc. On the other hand, IgM antibody to total histones tended to be increased in lSSc when compared with that in dSSc. Although SSc showed various antihistone specificities, H2B, H2A-H2B, (H2A-H2B)-dsDNA were main antigens recognised by IgG antibodies in both lSSc and dSSc. Although IgM antibodies to H2B and H2A-H2B were also detected in both lSSc and dSSc, serum samples from lSSc patients exhibited highest IgM reactivity with H1.
CONCLUSION—SSc may be included among conditions in which heterogeneous antihistone antibodies are produced. IgM antibodies to the most accessible histone H1 may be related to mild clinical features (lSSc) and IgG antibodies to the inner core molecules of native histone such as H2B or complexes including H2B may be associated with severe clinical features (dSSc) in Ssc.

 Keywords: histone; antibody; systemic sclerosis; enzyme linked immunosorbent assay
PMCID: PMC1752726  PMID: 9797552
23.  Cartilage oligomeric matrix protein-induced complement activation in systemic sclerosis 
Arthritis Research & Therapy  2013;15(6):R215.
Complexes between cartilage oligomeric matrix protein (COMP) and the complement activation product C3b have been found in the circulation of patients with rheumatoid arthritis and systemic lupus erythematosus. In systemic sclerosis (SSc) COMP expression in the skin is upregulated both in lesional and non-lesional skin, which is also reflected in an increased amount of circulating COMP. We investigated the presence of COMP-C3b complexes in serum and skin biopsies of patients with SSc.
The presence of COMP and COMP-C3b complexes in the serum of 80 patients with limited cutaneous SSc (lcSSc, n = 40) and diffuse cutaneous SSc (dcSSc, n = 40) and 97 healthy controls was measured by ELISA and correlated to different clinical parameters. Samples were collected both at baseline and after three to five years to assess longitudinal changes in COMP-C3b complex levels. Furthermore, skin biopsies from seven patients with dcSSc and three healthy controls were analyzed for expression of COMP and deposition of C3b and IgG.
Serum levels of COMP-C3b were found to be elevated in both dcSSc and lcSSc compared to healthy controls and decreased at the second measurement in patients on immunosuppressive therapy. No co-localization of COMP and C3b was found in the skin biopsies, indicating that the COMP-C3b complexes are formed upon release of COMP into the circulation.
COMP-C3b complexes are found in the serum of patients with SSc. The lack of co-localization between COMP and C3b in the skin suggests that COMP does not drive complement activation in the skin in SSc.
PMCID: PMC3978716  PMID: 24330664
24.  Maternal microchimerism in patients with biliary atresia 
Chimerism  2012;3(2):37-39.
Maternal-fetal cellular trafficking during pregnancy results in bidirectional microchimerism with potentially long-term consequences for the mother and her fetus. Exposure of the fetus to maternal cells results in tolerance to non-inherited maternal antigens (NIMA) and may therefore impact transplant outcomes. We investigated the rates of graft failure and retransplantation after parental liver transplantation in pediatric recipients with biliary atresia (BA), a disease with high levels of maternal microchimerism. We observed significantly lower rates of graft failure and retransplantation in BA recipients of maternal livers compared with BA recipients of paternal livers. Importantly, recipients without BA had equivalent transplant outcomes with maternal and paternal organs, suggesting that increased maternal microchimerism in BA patients may be the underlying etiology for tolerance. These results support the concept that prenatal exposure to NIMA may have consequences for living-related organ transplantation.
PMCID: PMC3442810  PMID: 22772071
biliary atresia; maternal-fetal cellular trafficking; microchimerism; tolerance
25.  Polymorphism of immunoglobulin enhancer element HS1,2A: allele *2 associates with systemic sclerosis. Comparison with HLA‐DR and DQ allele frequency 
Annals of the Rheumatic Diseases  2007;66(9):1210-1215.
To investigate the relationship of the polymorphic enhancer HS1,2 central to the 3′ enhancer complex regulatory region (IgH3′EC) of the immunoglobulin heavy chain genes with systemic sclerosis (SSc) disease and compare it with HLA‐DR and DQ associations.
A total of 116 patients with SSc were classified as diffuse (dSSc) or limited (lSSc), and as carriers of antitopoisomerase I (anti‐Scl70) or anticentromere (ACA) antibodies. Allele and genotype frequencies were assessed in the population as a whole and in the two major subsets, dSSc and lSSc. The concentration of peripheral blood immunoglobulin levels was also determined and analysed according to the genotypes.
The analysis of genotypes for the four alleles of the HS1,2A enhancer showed an increased frequency of allele *2 in the SSc cohort highly significant versus controls (57% vs. 40%, p<0.0001). Considering the autoantibody pattern, we found that the frequency of the 2/2 genotype was increased in ACA+ patients (42%) and anti‐Scl70+ patients (31%) compared with the control group (15%). The differences of allelic frequencies among dSSc versus lSSc or ACA+ versus anti‐Scl70+ patients were not significant, although highly significant when comparing each subgroup with the control group. HLA‐DRB1*11 and DQB1*03 associated with SSc. No association was seen between HS1,2A enhancer polymorphism and HLA alleles.
These data confirm there was an increased risk of having SSc in carriers of allele *2, suggesting an intriguing function of this polymorphism for B‐cell regulation.
PMCID: PMC1955163  PMID: 17392350

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