scholarly journals An open-label study to evaluate biomarkers and safety in systemic sclerosis patients treated with paquinimod

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Roger Hesselstrand ◽  
Jörg H. W. Distler ◽  
Gabriela Riemekasten ◽  
Dirk M. Wuttge ◽  
Marie Törngren ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Type I ◽  
Type I Ifn ◽  
Open Label ◽  
Reactive Protein ◽  
Before And After ◽  
Modified Rodnan Skin Score ◽  
Skin Biopsies ◽  
Rank 2

Abstract Objectives To evaluate the changes in disease-related biomarkers and safety of paquinimod, an oral immunomodulatory compound, in patients with systemic sclerosis (SSc). Methods In this open-label, single-arm, multicenter study, SSc patients with a rapidly progressive disease received paquinimod for 8 weeks. Blood and skin biopsies were collected at baseline, during treatment, and at follow-up for the analyses of type I interferon (IFN) activity, chemokine (C-C motif) ligand 2 (CCL2), and the number of myofibroblasts. The safety of paquinimod was evaluated throughout the study. Results Nine SSc patients were enrolled and completed the study treatment with paquinimod at 3 mg/day for 8 weeks. After the treatment, a reduction of type I IFN activity in the plasma from one patient with elevated baseline IFN activity was recorded. A trend towards reduced IFN activity in the skin after treatment was also observed in patients. The serum level of CCL2 was reduced in 7 of 9 patients after paquinimod treatment. There was a median reduction of 10% of the number of myofibroblasts in skin biopsies at week 8 compared to baseline. No change in modified Rodnan skin score and quality of life was detected in the study. Reported adverse events (AEs) were mild to moderate and expected with the most common being arthralgia (n = 3) and headache (n = 3), and C-reactive protein (CRP) increase. Conclusions Analysis of biomarkers before and after treatment suggest reduced type I IFN activity and reduced number of myofibroblasts in lesional skin. Paquinimod was overall well tolerated with mild to moderate and expected AEs. Trial registration ClinicalTrials.gov, NCT01487551. Registered on 7 September 2011

scholarly journals Impact of a structured, group-based running programme on clinical, cognitive and social function in youth and adults with complex mood disorders: a 12-week pilot study

2019 ◽  
Vol 5 (1) ◽  
pp. e000521
Author(s):  
Laura E Keating ◽  
Suzanna Becker ◽  
Katie McCabe ◽  
Jeff Whattam ◽  
Laura Garrick ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Mood Disorders ◽  
Exercise Intervention ◽  
Bodily Pain ◽  
Cognitive Outcomes ◽  
Open Label ◽  
Mood Symptoms ◽  
Before And After ◽  
The Impact

BackgroundIndividuals with mood disorders often report lingering health-related quality of life (HRQOL) and social and cognitive impairments even after mood symptoms have improved. Exercise programmes improve mood symptoms in patients, but whether exercise improves functional outcomes in patients with difficult-to-treat mood disorders remains unknown.DesignWe evaluated the impact of a 12-week structured running programme on cognitive, social and quality-of-life outcomes in participants with difficult-to-treat mood disorders.MethodsIn a prospective, open-label study, patients referred to the St Joseph’s Healthcare HamiltonTeam Unbreakablerunning programme for youth and adults with mood disorders completed a comprehensive assessment battery before and after the 12-week exercise intervention.ResultsWe collected preintervention and postintervention data from 18 participants who improved on the general health, vitality, role of emotions, social functioning and mental health (all p≤0.01) HRQOL subscales. Performance improved on cognitive tests that assessed working memory and processing speed (p≤0.04); there were no improvements in complex executive functioning tasks. Regression analyses indicated that younger age, shorter illness duration and reduced bodily pain predicted social and cognitive outcomes.ConclusionParticipation in a group-based, structured running programme was associated with improved HRQOL and social and cognitive function.

Upregulation of Myxovirus-resistance Protein A: A Possible Marker of Type I Interferon Induction in Systemic Sclerosis

2008 ◽  
Vol 35 (11) ◽  
pp. 2192-2200 ◽  
Author(s):  
PAOLO AIRÒ ◽  
CLAUDIA GHIDINI ◽  
CINZIA ZANOTTI ◽  
MIRKO SCARSI ◽  
ROBERTO CATTANEO ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Type I Interferon ◽  
Severe Disease ◽  
Protein A ◽  
Digital Ulcers ◽  
Type I ◽  
Healthy Controls ◽  
Type I Ifn ◽  
Resistance Protein ◽  
Reliable Marker

ObjectiveTo examine whether myxovirus-resistance protein A (MxA) mRNA expression, commonly considered a reliable marker of Type I interferon (IFN) bioactivity, is modified in patients with systemic sclerosis (SSc); if it is associated to specific clinical features; and if its modulation is accompanied by modulation of mRNA for the Type I IFN receptor (IFNAR).MethodsQuantification of mRNA for MxA and the subunit IFNAR1 and isoforms of IFNAR2 was performed by real-time polymerase chain reaction in 50 patients with SSc. Results were compared with those obtained from healthy controls and patients with another autoimmune disease such as multiple sclerosis.ResultsLevels of MxA mRNA above the 99th percentile of values found in healthy controls were observed in 9 out of 50 patients with SSc (p < 0.001). Induced MxA expression was significantly associated with some features of more severe disease, such as lower forced vital capacity and the presence of ischemic digital ulcers. No differences in the levels of IFNAR were found within MxA-induced and MxA-non-induced patients, but there was a direct correlation between levels of MxA and the soluble isoform of IFNAR2.ConclusionOur results show induction of MxA expression in some patients with SSc, which correlates with the presence of ischemic ulcers and other signs of worse disease, suggesting a potential role of Type I IFN in the pathogenesis of this disease and/or its complications.

scholarly journals Interferon regulatory factor 7 (IRF7) represents a link between inflammation and fibrosis in the pathogenesis of systemic sclerosis

2019 ◽  
Vol 78 (11) ◽  
pp. 1583-1591 ◽  
Author(s):  
Minghua Wu ◽  
Brian Skaug ◽  
Xiongjie Bi ◽  
Tingting Mills ◽  
Gloria Salazar ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Interferon Regulatory Factor ◽  
Dermal Fibroblasts ◽  
Type I ◽  
Type I Ifn ◽  
Hydroxyproline Content ◽  
Regulatory Factor ◽  
Dermal Fibrosis ◽  
Interferon Regulatory Factor 7

ObjectivesThere is considerable evidence that implicates dysregulation of type I interferon signalling (or type I IFN signature) in the pathogenesis of systemic sclerosis (SSc). Interferon regulatory factor 7 (IRF7) has been recognised as a master regulator of type I IFN signalling. The objective of this study was to elucidate the role of IRF7 in dermal fibrosis and SSc pathogenesis.MethodsSSc and healthy control skin biopsies were investigated to determine IRF7 expression and activation. The role of IRF7 in fibrosis was investigated using IRF7 knockout (KO) mice in the bleomycin-induced and TSK/+mouse models. In vitro experiments with dermal fibroblasts from patients with SSc and healthy controls were performed.ResultsIRF7 expression was significantly upregulated and activated in SSc skin tissue and explanted SSc dermal fibroblasts compared with unaffected, matched controls. Moreover, IRF7 expression was stimulated by IFN-α in dermal fibroblasts. Importantly, IRF7 co-immunoprecipitated with Smad3, a key mediator of transforming growth factor (TGF)-β signalling, and IRF7 knockdown reduced profibrotic factors in SSc fibroblasts. IRF7 KO mice demonstrated attenuated dermal fibrosis and inflammation compared with wild-type mice in response to bleomycin. Specifically, hydroxyproline content, dermal thickness as well as Col1a2, ACTA2 and interleukin-6 mRNA levels were significantly attenuated in IRF7 KO mice skin tissue. Furthermore, IRF7 KO in TSK/+mice attenuated hydroxyproline content, subcutaneous hypodermal thickness, Col1a2 mRNA as well as α-smooth muscle actin and fibronectin expression.ConclusionsIRF7 is upregulated in SSc skin, interacts with Smad3 and potentiates TGF-β-mediated fibrosis, and therefore may represent a promising therapeutic target in SSc.

Additional Treatment for Digital Ulcers in Patients with Systemic Sclerosis: A Prospective, Open-Label, Multi-Arm Study for the use of Platelet-Rich Plasma-Lipofilling and Ultrasound-Based Treatments

2021 ◽  
Author(s):  
ROBERTO PIRRELLO ◽  
CLAUDIA SCHINOCCA ◽  
DALILA SCATURRO ◽  
CHIARA RIZZO ◽  
PIETRO TERRANA ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Platelet Rich Plasma ◽  
Additional Treatment ◽  
Fat Grafting ◽  
Ultrasound Treatment ◽  
Digital Ulcers ◽  
Open Label ◽  
Group 3 ◽  
Group 2

Abstract Background: Local treatments such as ultraviolet-A (UVA) phototherapy, topical calcitriol, injection of autologous fat grafting, Platelet-Rich Plasma (PRP), hyaluronic acid (HA) and local ultrasound (US) treatment are considered alternative approaches for skin involvement in Systemic sclerosis (SSc).The aim of our study was to evaluate the efficacy of PRP injection and lipofilling or local ultrasound in the treatment of SSc-related digital ulcers (DUs). Methods: We enrolled 28 patients with SSc. At baseline time (T0), all patients were treated with Iloprost intravenous infusions. Then, six patients (group 1) received a first inoculation of PRP, after 15 days a second inoculation of PRP and after 15 days a third of lipofilling. Other six patients (group 2) received the three consecutive injections associated with a maintenance therapy with additional injections of PRP every 30 days for 12 months. Six patients continued only the Iloprost therapy (controls). Ten patients (group 3) underwent medical sessions with ultrasound treatment for 10 days. Clinical evaluation was assessed at baseline, after 3 and 12 months of treatment for all patients.Results: In our study have shown an improvement in cutaneous and microvascular level, in quality of life, in mobility of extremities of upper limbs and a reduction of administration of Iloprost after PRP-Lipofilling and US treatment.Conclusions: Our findings suggest that PRP, coupled with lipofilling, and ultrasound treatment in SSc patients, can be considered additional procedures in the management of DUs.

ID: 132: LUPUS KERATINOCYTES ARE PRIMED BY AN AUTOCRINE TYPE I INTERFERON LOOP TO ROBUSTLY SECRETE IL-6

2016 ◽  
Vol 64 (4) ◽  
pp. 976.2-977
Author(s):  
JN Stannard ◽  
TJ Reed ◽  
JM Kahlenberg ◽  
EM Myers ◽  
L Lowe ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Inflammatory Cytokine ◽  
Cutaneous Lupus Erythematosus ◽  
Type I ◽  
Healthy Controls ◽  
University Of Michigan ◽  
Type I Ifn ◽  
Skin Biopsies ◽  
The University ◽  
Cutaneous Lupus

BackgroundCutaneous lupus erythematosus (CLE) is a disfiguring disease that can affect up to 70% of patients with systemic lupus. Treatment modalities are often ineffective and flares are frequent. Interleukin-6 (IL-6) is a pro-inflammatory cytokine which has gotten recent attention in SLE as IL-6 is increased in the serum of active patients and blockade of IL-6 is therapeutic in murine lupus models and phase I human trials. The source of IL-6 in CLE remains unclear.MethodsAll studies were approved by the University of Michigan Internal Review Board (IRB# 72843 and 66116 to JMK). RNA was isolated from formalin fixed, paraffin-embedded biopsies of CLE rashes, which were obtained from the University of Michigan Pathology database. Real-time PCR was used to determine the expression level of the myxovirus (influenza virus) resistance 1 (MX-1) and interleukin-6 (IL6) genes. Biopsies were stained for IL-6 using immunohistochemistry. Skin biopsies were obtained from uninvolved skin of SLE patients with a history of cutaneous involvement or healthy controls followed by isolation and culture of keratinocytes. At confluence, cultures were treated with various concentrations of TLR ligands or UVB and IL-6 release was measured via ELISA. Blockade of type I IFN signaling was completed via monoclonal antibody to the type I IFN receptor.ResultsReal-time PCR analysis of subacute cutaneous lupus erythematosus (sCLE) (n=21) and discoid (DLE) (n=22) rashes demonstrated a significant upregulation of both the IFN-regulated gene, MX1, and the pro-inflammatory cytokine IL-6 when compared with control samples (n=9). Immunohistochemical analysis of skin biopsies confirmed upregulation of IL-6 in the epidermis when compared to control. Keratinocytes from healthy skin of lupus patients produced significantly more IL-6 when stimulated by TLR2, 3 or 4 agonists or exposed to UVB radiation when compared to identical passage keratinocytes from healthy controls. Treatment of control keratinocytes with IFNα increased their IL-6 production and blockade of type I IFNs in the culture media of SKE keratinocytes downregulated the secretion of IL-6.ConclusionsIL-6 is increased at the RNA and protein level within cutaneous lupus biopsies when compared to healthy control skin. Keratinocytes are a major producer of IL-6 in the skin and lupus keratinocytes have enhanced production of IL-6 in response to TLR ligands and UV radiation. Exposure to type I IFN can increase IL-6 production in keratinocytes. SLE-derived keratinocytes downregulate IL-6 production in the presence of tonic blockade of the type I IFN receptor. These data suggest that the epidermis, which is an important barrier for environmental insults, is primed for IL-6 production by autocrine type I IFN production and that this may be one mechanism by which factors such as UV exposure may trigger rash development. Further investigations should focus on the pathogenic significance of IL-6 upregulation in the skin and whether targeting this pathway will have an impact on cutaneous disease activity.

scholarly journals Neutralizing autoantibodies to type I IFNs in >10% of patients with severe COVID-19 pneumonia hospitalized in Madrid, Spain

2021 ◽  
Author(s):  
Jesús Troya García ◽  
Paul Bastard ◽  
Laura Planas-Serra ◽  
Pablo Ryan ◽  
Montse Ruíz ◽  
...  
Keyword(s):  
Severe Pneumonia ◽  
University Hospital ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Protein Levels ◽  
Reactive Protein ◽  
Risk Of Death ◽  
Type I Ifns ◽  
Increased Risk

Abstract Background: In a recent study, autoantibodies neutralizing type I interferons (IFNs) were present in at least 10% of cases of critical COVID-19 pneumonia. These autoantibodies neutralized most type I IFNs but rarely IFN-beta.Objectives: We aimed to define the prevalence of autoantibodies neutralizing type I IFN in a cohort of patients with severe COVID-19 pneumonia treated with IFN-beta-1b during hospitalization and to analyze their impact on various clinical variables and outcomes.Methods: We analyzed stored serum/plasma samples and clinical data of COVID-19 patients treated subcutaneously with IFN-beta-1b from March to May 2020, at the Infanta Leonor University Hospital in Madrid, Spain. Results: The cohort comprised 47 COVID-19 patients with severe pneumonia, 16 of whom (34%) had a critical progression requiring ICU admission. The median age was 71 years, with 28 men (58.6%). Type I IFN-alpha- and omega-neutralizing autoantibodies were found in 5 of 47 patients with severe pneumonia or critical disease (10.6%). The autoantibodies did not neutralize IFN-beta. No demographic, comorbidity, or clinical differences were seen between individuals with or without autoantibodies. We found a significant correlation between the presence of neutralizing autoantibodies and higher C-reactive protein levels (p=5.10e-03) and lower lymphocyte counts (p=1.80e-02). Survival analysis suggested that neutralizing autoantibodies may increase the risk of death (4/5, 80% vs 12/42, 28.5%).Conclusion: Autoantibodies neutralizing type I IFN underlie severe/critical COVID-19 stages in at least 10% of cases, correlate with increased C-RP and lower lymphocyte counts, and confer a trend towards increased risk of death. Subcutaneous IFN-beta treatment of hospitalized patients did not seem to improve clinical outcome. Studies of earlier, ambulatory IFN-beta treatment are warranted.

scholarly journals Correlation Between Serum C-Reactive Protein (CRP) and Soluble Cd40 Ligand (sCD40L) with Disease Activity by Modified Rodnan Skin Score (mRSS) in Systemic Sclerosis Patients in Indonesia

2018 ◽  
Vol 10 (2) ◽  
Author(s):  
Widi Palupi Ayu Padmandani ◽  
Sumartini Dewi ◽  
Laniyati Hamijoyo
Keyword(s):  
Systemic Sclerosis ◽  
Disease Activity ◽  
Inflammatory Process ◽  
Pearson Correlation ◽  
Cd40 Ligand ◽  
C Reactive Protein ◽  
Soluble Cd40 Ligand ◽  
Skin Score ◽  
Reactive Protein ◽  
Modified Rodnan Skin Score

Introduction: Systemic Sclerosis (SSc) is a chronic autoimmune disease which presents immunological, endothelial dysfunction, skin and organs fibrosis. The inflammatory process is an important pathophysiology of systemic sclerosis. Disease activity assessment using clinical parameters of Modified Rodnan Skin Score (mRSS) changes and inflammatory laboratory parameters of C-Reactive Protein (CRP), Erytrocyte Sedimentation Rate (ESR) and soluble CD40 ligand. The European Scleroderma Study Group (EscSG) Activity Index uses CRP. CRP is higher sensitivity and specificity than ESR (80% and 91.2%). The study aims to evaluate the correlation between CRP and sCD40L with disease activity by mRSS.Methods: This research was a cross-sectional study, and data of mRSS and sCD40L were obtained from the study, "Blind Clinical Trials Extract Ciplukan Herbs on Clinical Improvement of Skin Disorders, Inflammatory Process, Immunology and Fibrosis in Scleroderma Patients”. CRP examination was done by using the rest samples of the study, conducted in December 2017. Data analysis with Rank-Spearman and Pearson Correlation..Result: There were fifty-eight subjects with mean age 38 ± 11 years old. Most of subjects were female (94.8%) and with a late disease duration > 2 years (74.1 %). Subjects consisted of 35 (60.3%) diffuse SSc and 23 (39.7 %) limited SSc. CRP was measured by Turbidimetric Immunoassay. Median (range) CRP serum was 2.89 (0.16–17.29) mg/L, while the median of sCD40L was 6457 (1018–17976) pg/mL, and the median of mRSS was 17 (4–36). There was no correlation between CRP and sCD40L with mRSS (r = -0.134, p = 0.167; and r = 0.023, p = 0.433).Conclusion: There was no correlation between CRP and sCD40L serum with mRSS in systemic sclerosis patients.

scholarly journals Pilot Study of Anti-Th2 Immunotherapy for the Treatment of Breast Cancer-Related Upper Extremity Lymphedema

Biology ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 934
Author(s):  
Babak J. Mehrara ◽  
Hyeung Ju Park ◽  
Raghu P. Kataru ◽  
Jacqueline Bromberg ◽  
Michelle Coriddi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neutralizing Antibody ◽  
Treatment Withdrawal ◽  
Th2 Cells ◽  
Type Iii Collagen ◽  
Secondary Lymphedema ◽  
Before And After ◽  
History Of ◽  
Skin Biopsies

Recent studies suggest that Th2 cells play a key role in the pathology of secondary lymphedema by elaborating cytokines such as IL4 and IL13. The aim of this study was to test the efficacy of QBX258, a monoclonal IL4/IL13 neutralizing antibody, in women with breast cancer–related lymphedema (BCRL). We enrolled nine women with unilateral stage I/II BCRL and treated them once monthly with intravenous infusions of QBX258 for 4 months. We measured limb volumes, bioimpedance, and skin tonometry, and analyzed the quality of life (QOL) using a validated lymphedema questionnaire (Upper Limb Lymphedema 27, ULL-27) before treatment, immediately after treatment, and 4 months following treatment withdrawal. We also obtained 5 mm skin biopsies from the normal and lymphedematous limbs before and after treatment. Treatment was well-tolerated; however, one patient with a history of cellulitis developed cellulitis during the trial and was excluded from further analysis. We found no differences in limb volumes or bioimpedance measurements after drug treatment. However, QBX258 treatment improved skin stiffness (p < 0.001) and improved QOL measurements (Physical p < 0.05, Social p = 0.01). These improvements returned to baseline after treatment withdrawal. Histologically, treatment decreased epidermal thickness, the number of proliferating keratinocytes, type III collagen deposition, infiltration of mast cells, and the expression of Th2-inducing cytokines in the lymphedematous skin. Our limited study suggests that immunotherapy against Th2 cytokines may improve skin changes and QOL of women with BCRL. This treatment appears to be less effective for decreasing limb volumes; however, additional studies are needed.

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