Objective
Recent studies have highlighted that systemic lupus erythematosus (SLE) is characterized by different types of symptoms: type 1 symptoms related to inflammation and disease activity and ...type 2 symptoms such as fatigue, anxiety-depression, and pain. Our aim was to investigate the relation between type 1 and type 2 symptoms, and their impact on health-related quality of life (HRQoL) in SLE.
Methods
A literature review was conducted about disease activity/type1 and type 2 symptoms. Articles in English published after 2000 were located on Medline via Pubmed. The articles chosen evaluated at least one type 2 symptom or HRQoL using a validated scale in adult patients.
Results
Overall, 182 articles were analyzed and 115 were retained including 21 randomized, controlled trials and corresponding to 36 831 patients. We found that in SLE, inflammatory activity/type 1 symptoms were mostly uncorrelated with type 2 symptoms and/or HRQoL. Several studies even showing an inverse relationship. No or weak correlation was observed in 85, 3% (92, 6%), 76, 7% (74, 4%) and 37, 5% (73, 1%) of studies (patients) for fatigue, anxiety-depression, and pain, respectively. For HRQoL, no or weak correlation was observed in 77, 5% of studies (88% of patients).
Conclusion
Type 2 symptoms are poorly correlated with inflammatory activity/type 1 symptoms in SLE. Possible explanations and implications for clinical care and therapeutic evaluation are discussed.
Systemic sclerosis (SSc) is a complex autoimmune disease characterized by a functional and structural alteration of the microvascular network associated with cutaneous and visceral fibrosis lesions. ...Conventional therapies are based on the use of immunomodulatory molecules and symptomatic management but often prove to be insufficient, particularly for patients suffering from severe and rapidly progressive forms of the disease. In this context, cellular therapy approaches could represent a credible solution with the goal to act on the different components of the disease: the immune system, the vascular system and the extracellular matrix. The purpose of this review is to provide an overview of the cellular therapies available for the management of SSc. The first part will focus on systemically injected therapies, whose primary effect is based on immunomodulatory properties and immune system resetting, including autologous hematopoietic stem cell transplantation and intravenous injection of mesenchymal stem cells. The second part will discuss locally administered regenerative cell therapies, mainly derived from adipose tissue, developed for the management of local complications as hand and face disabilities.
We aimed to develop a systemic sclerosis (SSc) subtypes classifier tool to be used at the patient's bedside. We compared the heart rate variability (HRV) at rest (5-min) and in response to ...orthostatism (5-min) of patients (n = 58) having diffuse (n = 16, dcSSc) and limited (n = 38, lcSSc) cutaneous forms. The HRV was evaluated from the beat-to-beat RR intervals in time-, frequency-, and nonlinear-domains. The dcSSc group differed from the lcSSc group mainly by a higher heart rate (HR) and a lower HRV, in decubitus and orthostatism conditions. Stand-up maneuver lowered HR standard deviation (sd_HR), the major axis length of the fitted ellipse of Poincaré plot of RR intervals (SD2), and the correlation dimension (CorDim) in the dcSSc group while increased these HRV indexes in the lcSSc group (p = 0.004, p = 0.002, and p = 0.004, respectively). We identified the 5 most informative and discriminant HRV variables. We then compared 341 classifying models (1 to 5 variables combinations × 11 classifier algorithms) according to mean squared error, logloss, sensitivity, specificity, precision, accuracy, area under curve of the ROC-curves and F1-score. F1-score ranged from 0.823 for the best 1-variable model to a maximum of 0.947 for the 4-variables best model. Most specific and precise models included sd_HR, SD2, and CorDim. In conclusion, we provided high performance classifying models able to distinguish diffuse from limited cutaneous SSc subtypes easy to perform at the bedside from ECG recording. Models were based on 1 to 5 HRV indexes used as nonlinear markers of autonomic integrated influences on cardiac activity.
Large-vessel involvement (LVI) in giant cell arteritis (GCA) includes different clinical and imaging patterns that are rarely described separately at diagnosis and whose specific cardiovascular ...outcomes are unknown.
We conducted a nationwide retrospective study and included GCA patients with LVI demonstrated on imaging at diagnosis between 2007 and 2017. We analyzed the prognosis of three different imaging patterns of LVI present at diagnosis, with some of them overlapping but with the first one present in all patients: 1) inflammation of the aorta and/or its branches; 2) dilation of the aorta; and 3) stenosis of the aortic branches. A control group of GCA patients without LVI was constituted.
We included 183 patients with LVI and 105 controls without LVI. Altogether, among the 183 patients who all showed inflammation of the aorta and/or its main branches, concomitant aortic dilation and large-vessel stenosis were observed in 27 (15%) and 55 (30%) patients, respectively. During the follow-up period, new cardiovascular events occurred in 49% and 11% of LVI patients and controls, respectively (p < 0.0001). Inflammation of the aorta and/or its branches (HR: 3.42 2.09–5.83, p < 0.0001) and large-artery stenosis (HR: 2.75 1.80–4.15, p < 0.0001) were independent predictive factors of new cardiovascular events. Conversely, the use of an immunosuppressant besides corticosteroids was a protective factor against new cardiovascular events (HR: 0.44 0.29–0.66, p < 0.0001) and the development of aortic dilation (HR: 0.43 0.23–0.77, p = 0.005).
This study suggests different forms of cardiovascular events according to the initial imaging pattern of LVI.
•Large-vessel involvements include aortitis, aorta dilation and vascular stenoses.•These patterns exhibit different outcomes and prognoses.•More cardiovascular events occur in patients with initial large-vessel involvement.•Large-vessel stenosis was associated with the poorest outcomes.•Immunosuppressants might have a protective impact on new cardiovascular events.
To estimate the prevalence, determine the subgroups at risk, and the outcomes of patients with systemic sclerosis (SSc) and gastric antral vascular ectasia (GAVE).
We queried the European League ...Against Rheumatism Scleroderma Trials and Research (EUSTAR) network for the recruitment of patients with SSc-GAVE. Each case was matched for cutaneous subset and disease duration with 2 controls with SSc recruited from the same center, evaluated at the time the index case made the diagnosis of GAVE. SSc characteristics were recorded at the time GAVE occurred and the last observation was collected to define the outcomes.
Forty-nine patients with SSc and GAVE were included (24 with diffuse cutaneous SSc) and compared to 93 controls with SSc. The prevalence of GAVE was estimated at about 1% of patients with SSc. By multivariate analysis, patients with SSc-GAVE more frequently exhibited a diminished (< 75%) DLCO value (OR 12.8; 95% CI 1.9-82.8) despite less frequent pulmonary fibrosis (OR 0.2; 95% CI 0.1-0.6). GAVE was also associated with the presence of anti-RNA-polymerase III antibodies (OR 4.6; 95% CI 1.2-21.1). SSc-GAVE was associated with anemia (82%) requiring blood transfusion (45%). Therapeutic endoscopic procedures were performed in 45% of patients with GAVE. After a median followup of 30 months (range 1-113 months), survival was similar in patients with SSc-GAVE compared to controls, but a higher number of scleroderma renal crisis cases occurred (12% vs 2%; p = 0.01).
GAVE is rare and associated with a vascular phenotype, including anti-RNA-polymerase III antibodies, and a high risk of renal crisis. Anemia, usually requiring blood transfusions, is a common complication.
Interestingly, injection of sCD146 in bleomycin-treated CD146KO mice showed a significant reduction in dermal and epidermal thickness as compared with bleomycin condition (P = .003 and P < .0001, ...respectively; Fig 2, E-H), suggesting that sCD146 protects bleomycin-treated CD146KO mice from fibrosis development. Because the Wnt pathway is involved in SSc fibrogenesis6 and because interaction between CD146 and Wnt5a7 was recently described, we investigated the effects of CD146. ...we showed that CD146/CD146s modulates Wnt signaling. ...our data led us to propose CD146/sCD146 as a novel biomarker in SSc for the assessment of the disease activity. Patients with SSc (n = 50) (25%-75% percentile) Median age (y) 62 (56-71) Median disease duration (y) 13 (10-20) Male/female 06/44 Clinical features n (%) Diffuse cutaneous form∗ 23 (46) Ulcers, scars, gangrene 21 (42) Pulmonary fibrosis† 20 (40) Pulmonary arterial hypertension‡ 7 (14) Digestive involvement 39 (78) Kidney involvement 5 (10) Immunologic results n (%) Positive for antinuclear antibodies 50 (100) Centromeric staining (ACA) 18 (36) Homogeneous nucleoplasmic and nucleolar staining 15 (30) Nucleolar staining 7 (14) Homogeneous and speckled nucleoplasmic staining 8 (16) Speckled nucleoplasmic staining 2 (4) Positive for anti-topoisomerase I (anti-topo I) 25 (50) 1 A. Gabrielli, E.V. Avvedimento, T. Krieg, Scleroderma, N Engl J Med, Vol. 360, 2009, 1989-2003 2 N. Bardin, V. Moal, F. Anfosso, L. Daniel, P. Brunet, J. Sampol, Soluble CD146, a novel endothelial marker, is increased in physiopathological settings linked to endothelial junctional alteration, Thromb Haemost, Vol. 90, 2003, 915-920 3 N. Bardin, M. Blot-Chabaud, N. Despoix, A. Kebir, K. Harhouri, J.-P.
Grafted fat has many qualities of ideal filler; it is autologous, easily available, and naturally integrated into the host tissues. From a lipoaspirate, the adipose-tissue-derived stromal vascular ...fraction can be isolated, which is an excellent source of stem/stromal cells, endothelial progenitors, and immune cells. Fat grafting is being increasingly applied in autoimmune diseases, and this article focuses on systemic sclerosis, a rare autoimmune disease characterized by skin fibrosis and microvascular damage. The authors' approach of using fat graft in the face and adipose-tissue-derived stromal vascular fraction for hands is presented as innovative and promising therapy for patients with systemic sclerosis.
The pathophysiology of systemic sclerosis (SSc) involves early endothelial and immune activation, both preceding the onset of fibrosis. We previously identified soluble fractalkine and circulating ...endothelial microparticles (EMPs) as biomarkers of endothelial inflammatory activation in SSc. Fractalkine plays a dual role as a membrane-bound adhesion molecule expressed in inflamed endothelial cells (ECs) and as a chemokine involved in the recruitment, transmigration, and cytotoxic activation of immune cells that express CX3CR1, the receptor of fractalkine, namely CD8 and γδ T cells and natural killer (NK) cells. We aimed to quantify circulating cytotoxic immune cells and their expression of CX3CR1. We further investigated the expression profile of NK cells chemokine receptors and activation markers and the potential of NK cells to induce EC activation in SSc. We performed a monocentric study (NCT 02636127) enrolling 15 SSc patients 15 females, median age of 55 years (39-63), 11 limited cutaneous form and 4 diffuse and 15 healthy controls. Serum fractalkine levels were significantly increased in SSc patients. Circulating CD8 T cells numbers were decreased in SSc patients with no difference in their CX3CR1 expression. Circulating γδ T cells and NK cells numbers were preserved. CX3CR1 expression in CD8 and γδ T cells did not differ between SSc patients and controls. The percentage and level of CX3CR1 expression in NK cells were significantly lowered in SSc patients. Percentages of CXCR4, NKG2D, CD69-expressing NK cells, and their expression levels were decreased in NK cells. Conversely, CD16 level expression and percentages of CD16
NK cells were preserved. The exposure of human microvascular dermic EC line (HMVEC-d) to peripheral blood mononuclear cells resulted in similar NK cells degranulation activity in SSc patients and controls. We further showed that NK cells purified from the blood of SSc patients induced enhanced release of EMPs than NK cells from controls. This study evidenced a peculiar NK cells phenotype in SSc characterized by decreased chemokine and activation receptors expression, that might reflect NK cells involvement in the pathogenic process. It also highlighted the role of NK cells as a potent mechanism inducing endothelial activation through enhanced EMPs release.
To assess the prevalence and potential associations with the systemic sclerosis (SSc) phenotype of additional autoimmune diseases (AID).
A multicenter study was performed in France and Italy to ...recruit consecutive European Caucasian patients with SSc systematically assessed for the coexistence of predefined AID known to occur with connective tissue diseases.
We recruited 585 French and 547 Italian patients with SSc. Specific AID were found in 114/585 (19%) French and 179/547 (33%) Italians with SSc (p < 0.0001). Sjögren's syndrome and thyroiditis were the predominant AID in both cohorts (12% for Sjögren's syndrome and 6% for thyroiditis in the combined populations). The frequency of myositis, primary biliary cirrhosis, rheumatoid arthritis, and systemic lupus erythematosus was low (< 4%) and similar in both cohorts. The coexistence of at least 1 of the AID in the whole cohort was associated in multivariate analysis with the limited cutaneous subtype, the presence of antinuclear antibodies, and a lower prevalence of digital ulcers.
Our study shows that 21% of this large series of European Caucasian patients with SSc have developed at least 1 AID. This latter condition identified a subset of patients with milder disease. Thus, associations of AID and autoimmune background in SSc have to be considered for further therapeutic and biological investigations in SSc.
Adipose tissue is recognized as a valuable source of cells with angiogenic, immunomodulatory, reparative and antifibrotic properties and emerged as a therapeutic alternative for the regeneration and ...repair of damaged tissues. The use of adipose-tissue-based therapy is expanding in autoimmune diseases, particularly in Systemic Sclerosis (SSc), a disease in which hands and face are severely affected, leading to disability and a decrease in quality of life. Combining the advantage of an abundant supply of fat tissue and a high abundance of stem/stromal cells, fat grafting and adipose tissue-derived cell-based therapies are attractive therapeutic options in SSc. This review aims to synthesize the evidence to determine the effects of the use of these biological products for face and hands treatment in the context of SSc. This highlights several points: the need to use relevant effectiveness criteria taking into account the clinical heterogeneity of SSc in order to facilitate assessment and comparison of innovative therapies; second, it reveals some impacts of the disease on fat-grafting success; third, an important heterogeneity was noticed regarding the manufacturing of the adipose-derived products and lastly, it shows a lack of robust evidence from controlled trials comparing adipose-derived products with standard care.
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