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1.
Clin Rheumatol ; 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31916109

RESUMO

Although several genetic associations with scleroderma (SSc) are defined, very little is known on genetic susceptibility to SSc-associated interstitial lung disease (SSc-ILD). A number of common polymorphisms have been associated with SSc-ILD, but most have not been replicated in separate populations. Four SNPs in IRF5, and one in each of STAT4, CD226 and IRAK1, selected as having been previously the most consistently associated with SSc-ILD, were genotyped in 612 SSc patients, of European descent, of whom 394 had ILD. The control population (n = 503) comprised individuals of European descent from the 1000 Genomes Project. After Bonferroni correction, two of the IRF5 SNPs, rs2004640 (OR (95% CI)1.30 (1.10-1.54), pcorr = 0.015) and rs10488631 (OR 1.48 (1.14-1.92), pcorr = 0.022), and the STAT4 SNP rs7574865 (OR 1.43 (1.18-1.73), pcorr = 0.0015) were significantly associated with SSc compared with controls. However, none of the SNPs were significantly different between patients with SSc-ILD and controls. Two SNPs in IRF5, rs10488631 (OR 1.72 (1.24-2.39), pcorr = 0.0098), and rs2004640 (OR 1.39 (1.11-1.75), pcorr = 0.03), showed a significant difference in allele frequency between controls and patients without ILD, as did STAT4 rs7574865 (OR 1.86 (1.45-2.38), pcorr = 6.6 × 10-6). A significant difference between SSc with and without ILD was only observed for STAT4 rs7574865, being less frequent in patients with ILD (OR 0.66 (0.51-0.85), pcorr = 0.0084). In conclusion, IRF5 rs2004640 and rs10488631, and STAT4 rs7574865 were significantly associated with SSc as a whole. Only STAT4 rs7574865 showed a significant difference in allele frequency in SSc-ILD, with the T allele being protective against ILD.Key points• We confirm the associations of the IRF5 SNPs rs2004640 and rs10488631, and the STAT4 SNP rs7574865, with SSc as a whole.• None of the tested SNPs were risk factors for SSc-ILD specifically.• The STAT4 rs7574865 T allele was protective against the development of lung fibrosis in SSc patients.• Further work is required to understand the genetic basis of lung fibrosis in association with scleroderma.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31841044

RESUMO

Systemic sclerosis (SSc) is a complex, multi-organ, autoimmune disease. Lung fibrosis occurs in ~80% of patients with SSc; 25-30% develop progressive interstitial lung disease (ILD). The pathogenesis of fibrosis in SSc associated ILD (SSc-ILD) involves cellular injury, activation/differentiation of mesenchymal cells and morphological/biological changes in epithelial/endothelial cells. Risk factors for progressive SSc-ILD include older age, male sex, lung involvement on baseline high-resolution computed tomography, reduced diffusing capacity for carbon monoxide and reduced forced vital capacity. SSc-ILD is characterized by genetic risk architecture distinct from that associated with idiopathic pulmonary fibrosis (IPF). Presence of anti-Scl-70 antibodies and absence of anti-centromere antibodies indicate increased likelihood of progressive ILD. Elevated levels of serum Krebs von den Lungen-6 (KL6) and CRP are associated with SSc-ILD severity, although whether KL6 independently predicts SSc-ILD progression remains controversial. A promising prognostic indicator is serum chemokine (C-C motif) ligand 18. SSc-ILD shares similarities with IPF, although clear differences exist. Histologically, a non-specific interstitial pneumonia pattern is commonly observed in SSc-ILD, whereas IPF is defined by usual interstitial pneumonia. The course of SSc-ILD is variable, ranging from minor, stable disease to a progressive course, while all IPF patients experience progression of disease. Although appropriately treated SSc-ILD patients have better chances of stabilization and survival, a relentlessly progressive course, akin to IPF, is seen in a minority. Better understanding of cellular and molecular pathogenesis, genetic risk and distinctive features of SSc-ILD, and identification of robust prognostic biomarkers are needed for optimal disease management. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

3.
Artigo em Inglês | MEDLINE | ID: mdl-31841265

RESUMO

OBJECTIVES: Digital ulcers (DUs) are a major cause of disease-related morbidity and difficult to treat vascular complication of systemic sclerosis (SSc). Demonstrating treatment efficacy has traditionally focussed upon clinician assessment of DUs alone. No existing patient reported outcome (PRO) instrument captures the multi-faceted impact of SSc-DU. We report the findings of a multi-centre qualitative research study exploring the patient experience of SSc-DU. METHODS: Patient focus groups (FGs) were conducted across 3 scleroderma units, following a topic guide devised by SSc patients, experts and experienced qualitative researchers. A purposive sampling framework ensured the experiences of a diverse group of patients were captured. FGs were audio recorded, transcribed, anonymised, and analysed using inductive thematic analysis. We continued FGs until thematic saturation was achieved. RESULTS: Twenty-nine SSc patients with a history of DU disease participated in 4 FGs across the UK (Bath, Manchester and London). Five major inter-related themes (and sub-themes) were identified which encompass the patient experience of SSc-DUs: 'Disabling pain and hypersensitivity', 'Deep and broad-ranging emotional impact', 'Impairment of physical and social activity', 'Factors aggravating occurrence, duration and impact' and 'Mitigating, managing and adapting'. CONCLUSION: The patient experience of SSc-DU is multi-faceted and comprises a complex interplay of experiences associated with significant pain and morbidity. Patient experiences of SSc-DU are not captured using existing SSc-DU outcomes. Our findings shall inform the development of a novel PRO instrument to assess the severity and impact of SSc-DUs for use in future SSc-DU clinical trials.

4.
Semin Arthritis Rheum ; 49(3S): S3-S7, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31779848

RESUMO

Systemic sclerosis (scleroderma; SSc) is an autoimmune rheumatic disease with high clinical burden and unmet need due to connective tissue fibrosis and vascular damage. It has the highest case specific mortality of any rheumatic disease, with approximately half of patients diagnosed eventually dying as a direct result of SSc. There are no approved diseases modifying treatments. This is partly related to the difficulty of conducting clinical trials for regulatory approval. Traditionally skin thickness has been assessed using the modified Rodnan skin score (MRSS) that has been shown to correlate with survival and risk of complications in SSc. However recent trials have highlighted the limitations of MRSS which often improves over time, even on placebo. A new composite measure integrating changes in multiple domains of lung function, skin, patients and physician global and HAQ disability index has been developed, the CRISS (Composite Response Index for Systemic Sclerosis). This measure looks promising and has provisional acceptance by American College of Rheumatology (designated ACR CRISS) but is unlikely to be strongly persuasive to Health Authorities in isolation unless there are also clinically meaningful changes in relevant domains that reflect how patients feel, function or survive.

5.
Nat Commun ; 10(1): 4955, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31672989

RESUMO

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31680161

RESUMO

OBJECTIVES: Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations. METHODS: SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses. RESULTS: The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P < 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P < 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P < 0.001) diffuse skin involvement than had WP. AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P < 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P < 0.001; OR(BP) = 2.4, P < 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P < 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P < 0.001]. CONCLUSION: Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality.

7.
Arthritis Rheumatol ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31682743

RESUMO

OBJECTIVE: To describe the associations between autoantibodies, presentation and outcome among systemic sclerosis (SSc) patients. We propose a new SSc classification incorporating antibodies and cutaneous subset. METHODS: Survival analysis was used to assess the effect of antibodies on organ disease and death. RESULTS: The study included 1325 subjects. The ACA+ limited cutaneous (lc)SSc group (n=374) had the highest 20-year survival (65.3%), lowest incidence of clinically-significant pulmonary fibrosis (csPF, 8.5%) and scleroderma renal crisis (SRC, 0.3%), low cardiac SSc incidence (4.9%), while pulmonary hypertension (PH) frequency was similar to the cohort average. The anti-Scl70+ lcSSc (n=138) and diffuse cutaneous (dc)SSc groups (n=149) had the highest csPF incidence (86.1% and 84% at 15 years). The dcSSc group had the lowest survival (32.4%) and the second highest incidence of cardiac SSc (12.9%) at 20 years, while in the lcSSc group other complications were rare, demonstrating the lowest incidence of PH (6.9%) and second highest survival (61.8%). The anti-RNA polymerase+ group (n=147) had the highest incidence of SRC (28.1%). The anti-U3RNP+ group (n=56) had the highest PH (33.8%) and cardiac SSc incidence (13.2%). Among lcSSc patients with other autoantibodies (n=295), risk of SRC and cardiac SSc was low, while other outcomes were similar to the cohort average. DcSSc patients with other antibodies (n=166) had poor prognosis, with the second lowest survival (33.6%) and frequent organ complications. CONCLUSION: We highlight the importance of autoantibodies, cutaneous subset and disease duration when assessing SSc morbidity and mortality. Our classification may benefit disease monitoring and clinical trial design.

8.
Arthritis Res Ther ; 21(1): 217, 2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31655622

RESUMO

OBJECTIVE: The objective of this randomized, placebo-controlled, double-blind, parallel group, trial was to assess the effect of ambrisentan on mean pulmonary arterial pressure (mPAP) in patients with systemic sclerosis (SSc) and mildly elevated pulmonary hypertension (PH). METHODS: Thirty-eight SSc patients with mildly elevated mPAP at rest between 21 and 24 mmHg and/or > 30 mmHg during low-dose exercise were randomly assigned to treatment with either ambrisentan 5-10 mg/day or placebo. Right heart catheterization and further clinical parameters were assessed at baseline and after 6 months. The primary endpoint was the difference of mPAP change at rest between groups. RESULTS: After 6 months, the two groups did not differ in the primary endpoint (ambrisentan mPAP - 1 ± 6.4 mmHg vs. placebo - 0.73 ± 3.59 mmHg at rest, p = 0.884). However, three patients from the placebo group but none of the ambrisentan group progressed to SSc-associated pulmonary arterial hypertension. Furthermore, ambrisentan treatment showed significant improvements in the secondary endpoints cardiac index (CI) and pulmonary vascular resistance (PVR) at rest (CI 0.36 ± 0.66 l/min/m2 vs. - 0.31 ± 0.71 l/min/m2, p = 0.010; PVR - 0.70 ± 0.78 WU vs. 0.01 ± 0.71 WU, p = 0.012) and during exercise (CI 0.7 ± 0.81 l/min/m2 vs. - 0.45 ± 1.36 l/min/m2, p = 0.015; PVR - 0.84 ± 0.48 WU vs. - 0.0032 ± 0.34 WU, p < 0.0001). CONCLUSION: This is the first randomized, double-blind, placebo-controlled study testing the effect of ambrisentan in patients with mildly elevated mPAP and/or exercise PH. The primary endpoint change in mPAP did only tendentially improve in the ambrisentan group, but the significant improvement of other hemodynamic parameters points to a possible benefit of ambrisentan and will be helpful to design future trials. TRIAL REGISTRATION: www.ClinicalTrials.gov, unique identifier NCT: NCT02290613 , registered 14th of November 2014.

9.
Clin Rheumatol ; 38(12): 3669-3676, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31482318

RESUMO

INTRODUCTION: Raynaud's phenomenon (RP) is a common condition and causes pain, paraesthesia, ulceration and gangrene. Botulinum toxin A (Btx-A) is effective when injected via a digital palmar approach, in the treatment of severe RP. However, hand weakness resulting from lumbrical malfunction is a recognized complication. This study aimed to determine the effect of Btx-A injected via a dorsal approach. METHOD: Forty patients received 100 units of Btx-A, injected across both hands via a dorsal approach. Each patient had a baseline, 6- and 12-week hand assessment and thermographic image (FLIR E60bx) performed for the study. RESULTS: Eighty-eight percent of patients reported an improvement in symptoms including reduction in pain, improved colour change with reduced swelling and edema at 6 weeks. Of these patients, 80% reported an improvement in cold intolerance with a reduction in the frequency and severity of Raynaud's attacks. There was a significant improvement in both the DASH score (p = 0.001), Kapandji score (p = 0.001) and hand strength (p < 0.05). No patients reported weakness. Improvements in hand function and symptoms of RP were still evident at 12 weeks. CONCLUSIONS: Btx-A injected via a dorsal approach improves symptoms and reduces the number of RP. We have shown an effective non-surgical approach technique to treat RP.Key Points• Raynaud's phenomenon is a common vasospastic disorder of the digital vessels, which can cause severe pain, restrictions to hand function and ulceration.• Dorsal botulinum toxin type A injections can improve the symptoms of secondary Raynaud's phenomenon and hand function for approximately 3 months.

10.
Autoimmun Rev ; 18(11): 102394, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520797

RESUMO

OBJECTIVES: This study was designed to propose a simple "Fast Track algorithm" for capillaroscopists of any level of experience to differentiate "scleroderma patterns" from "non-scleroderma patterns" on capillaroscopy and to assess its inter-rater reliability. METHODS: Based on existing definitions to categorise capillaroscopic images as "scleroderma patterns" and taking into account the real life variability of capillaroscopic images described standardly according to the European League Against Rheumatism (EULAR) Study Group on Microcirculation in Rheumatic Diseases, a fast track decision tree, the "Fast Track algorithm" was created by the principal expert (VS) to facilitate swift categorisation of an image as "non-scleroderma pattern (category 1)" or "scleroderma pattern (category 2)". Mean inter-rater reliability between all raters (experts/attendees) of the 8th EULAR course on capillaroscopy in Rheumatic Diseases (Genoa, 2018) and, as external validation, of the 8th European Scleroderma Trials and Research group (EUSTAR) course on systemic sclerosis (SSc) (Nijmegen, 2019) versus the principal expert, as well as reliability between the rater pairs themselves was assessed by mean Cohen's and Light's kappa coefficients. RESULTS: Mean Cohen's kappa was 1/0.96 (95% CI 0.95-0.98) for the 6 experts/135 attendees of the 8th EULAR capillaroscopy course and 1/0.94 (95% CI 0.92-0.96) for the 3 experts/85 attendees of the 8th EUSTAR SSc course. Light's kappa was 1/0.92 at the 8th EULAR capillaroscopy course, and 1/0.87 at the 8th EUSTAR SSc course. CONCLUSION: For the first time, a clinical expert based fast track decision algorithm has been developed to differentiate a "non-scleroderma" from a "scleroderma pattern" on capillaroscopic images, demonstrating excellent reliability when applied by capillaroscopists with varying levels of expertise versus the principal expert and corroborated with external validation.


Assuntos
Algoritmos , Esclerodermia Localizada/diagnóstico , Escleroderma Sistêmico/diagnóstico , Humanos , Angioscopia Microscópica/métodos , Reprodutibilidade dos Testes
11.
Ann Rheum Dis ; 78(11): 1576-1582, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31391176

RESUMO

OBJECTIVES: To investigate the influence of vasodilator drugs on the occurrence of features depending on myocardial ischaemia/fibrosis (ventricular arrhythmias, Q waves, cardiac blocks, pacemaker implantation, left ventricular ejection fraction (LVEF) <55%, and/or congestive heart failure and sudden cardiac death) in systemic sclerosis (SSc). METHODS: 601 patients with SSc were enrolled from 1 December 2012 to 30 November 2015 and had a second visit 0.5-4 years apart. 153 received no vasodilators; 448 received vasodilator therapy (ie, calcium channel blockers and/or ACE inhibitors or angiotensin II receptor blockers or combinations of them), 89 of them being also treated with either endothelin receptor antagonists or PDE5 inhibitors or prostanoids. Associations between the occurrence of myocardial disease manifestations and any demographic, disease and therapeutic aspect were investigated by Cox regression analysis. A Cox frailty survival model with centre of enrolment as random effect was performed. RESULTS: During 914 follow-up patient-years, 12 ventricular arrhythmias, 5 Q waves, 40 cardiac blocks, 6 pacemaker implantations and 19 reduced LVEF and/or congestive heart failure (CHF) occurred. In multivariate Cox regression analysis, vasodilator therapy was associated with a lower incidence of ventricular arrhythmias (p=0.03); low-dose acetylsalicylic acid (ASA) with a lower incidence of cardiac blocks and/or Q waves and/or pacemaker implantation (p=0.02); active disease with a higher incidence of LVEF <55% and/or CHF and cardiac blocks and/or Q waves and/or pacemaker implantation (p=0.05). CONCLUSIONS: The present study might suggest a preventative effect on the occurrence of distinct myocardial manifestations by vasodilator therapy and low-dose ASA.

12.
JCI Insight ; 52019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31393855

RESUMO

It has been hypothesized that interleukin-1alpha (IL-1α) is released from damaged cardiomyocytes following myocardial infarction (MI) and activates cardiac fibroblasts via its receptor (IL-1R1) to drive the early stages of cardiac remodeling. This study aimed to definitively test this hypothesis using cell type-specific IL-1α and IL-1R1 knockout (KO) mouse models. A floxed Il1α mouse was created and used to generate a cardiomyocyte-specific IL-1α KO mouse line (MIL1AKO). A tamoxifen-inducible fibroblast-specific IL-1R1 hemizygous KO mouse line (FIL1R1KO) was also generated. Mice underwent experimental MI (permanent left anterior descending coronary artery ligation) and cardiac function was determined 4 weeks later by conductance pressure-volume catheter analysis. Molecular markers of remodeling were evaluated at various time points by real-time RT-PCR and histology. MIL1AKO mice showed no difference in cardiac function or molecular markers of remodeling post-MI compared with littermate controls. In contrast, FIL1R1KO mice showed improved cardiac function and reduced remodeling markers post-MI compared with littermate controls. In conclusion, these data highlight a key role for the IL-1R1/cardiac fibroblast signaling axis in regulating post-MI remodeling and provide support for the continued development of anti-IL-1 therapies for improving cardiac function after MI. Cardiomyocyte-derived IL-1α was not an important contributor to post-MI remodeling in this model.

13.
Arthritis Rheumatol ; 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31342624

RESUMO

OBJECTIVE: T cells play a key role in the pathogenesis of early systemic sclerosis. This study was undertaken to assess the safety and efficacy of abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS: In this 12-month, randomized, double-blind, placebo-controlled trial, participants were randomized 1:1 to receive either subcutaneous abatacept 125 mg or matching placebo, stratified by duration of dcSSc. Escape therapy was allowed at 6 months for worsening disease. The coprimary end points were change in the modified Rodnan skin thickness score (MRSS) compared to baseline and safety over 12 months. Differences in longitudinal outcomes were assessed according to treatment using linear mixed models, with outcomes censored after initiation of escape therapy. Skin tissue obtained from participants at baseline was classified into intrinsic gene expression subsets. RESULTS: Among 88 participants, the adjusted mean change in the MRSS at 12 months was -6.24 units for those receiving abatacept and -4.49 units for those receiving placebo, with an adjusted mean treatment difference of -1.75 units (P = 0.28). Outcomes for 2 secondary measures (Health Assessment Questionnaire disability index and a composite measure) were clinically and statistically significantly better with abatacept. The proportion of subjects in whom escape therapy was needed was higher in the placebo group relative to the abatacept group (36% versus 16%). In the inflammatory and normal-like skin gene expression subsets, decline in the MRSS over 12 months was clinically and significantly greater in the abatacept group versus the placebo group (P < 0.001 and P = 0.03, respectively). In the abatacept group, adverse events occurred in 35 participants versus 40 participants in the placebo group, including 2 deaths and 1 death, respectively. CONCLUSION: In this phase II trial, abatacept was well-tolerated, but change in the MRSS was not statistically significant. Secondary outcome measures, including gene expression subsets, showed evidence in support of abatacept. These data should be confirmed in a phase III trial.

14.
Curr Med Res Opin ; 35(11): 2015-2024, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31328965

RESUMO

Objective: Some patients with interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF) develop a progressive fibrosing phenotype. We investigated the diagnosis and management of non-IPF ILDs using data from a survey of physicians and from US insurance claims. Methods: Pulmonologists, rheumatologists and internists in France, Germany, Italy, Japan, Spain, UK and US who had managed ≥10 patients with non-IPF ILDs in the past year, including those with progressive fibrosing ILDs, completed an online survey. Data on US insurance and prescription claims were obtained from a repository that aggregates data on claims routed from providers or pharmacies to payers. Results: In May-June 2017, 243 pulmonologists, 203 rheumatologists and 40 internists completed an online survey. Respondents estimated that 18-32% of patients diagnosed with non-IPF ILDs develop progressive fibrosis and that time from symptom onset to death in these patients was 61-80 months. Drug treatment was given to 50-75% of patients with non-IPF progressive fibrosing ILDs. Reasons for patients not being treated included that physicians considered patients to have mild or slowly progressing disease, or did not believe that available treatments are effective or well tolerated. Corticosteroids were the preferred first-line treatment for all types of non-IPF ILD. There was considerable heterogeneity in preferences for second- and third-line treatments. US insurance claims data from 3823 patients indicated that, in 2016, 50-75% of patients with ILDs received drug treatment (mostly corticosteroids) for their ILD. Conclusions: Physicians estimate that 18-32% of patients diagnosed with non-IPF ILDs develop a progressive fibrosing phenotype and that these patients experience significant delays in the diagnosis of ILD and the detection of progressive fibrosis. Between 25% and 50% of patients with progressive fibrosing ILDs do not receive drug therapy. There is an unmet need for effective and well tolerated treatments for progressive fibrosing ILDs.

15.
PLoS One ; 14(7): e0218068, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31314805

RESUMO

Oro-facial fibrosis in systemic sclerosis (Scleroderma;SSc) has a major impact on mouth function, facial appearance, and patient quality of life. Lipotransfer is a method of reconstruction that can be used in the treatment of oro-facial fibrosis. The effect of this treatment not only restores oro-facial volume but has also been found to reverse the effects of oro-facial fibrosis. Adipose derived stem cells (ADSCs) within the engrafted adipose tissue have been shown to be anti-fibrotic in SSc and are proposed as the mechanism of the anti-fibrotic effect of lipotransfer. A cohort of 62 SSc patients with oro-facial fibrosis were assessed before and after stem cell enriched lipotransfer treatment. Clinical evaluation included assessment of mouth function using a validated assessment tool (Mouth Handicap in Systemic Sclerosis Scale-MHISS), validated psychological measurements and pre and post-operative volumetric assessment. In addition, to understand the mechanism by which the anti-fibrotic effect of ADSCs occur, SSc derived fibroblasts and ADSCs from this cohort of patients were co-cultured in direct and indirect culture systems and compared to monoculture controls. Cell viability, DNA content, protein secretion of known fibrotic mediators including growth factor- ß1 (TGF ß-1) and connective tissue growth factor (CTGF) using ELISA analysis and fibrosis gene expression using a fibrosis pathway specific qPCR array were evaluated. Mouth function (MHISS) was significantly improved (6.85±5.07) (p<0.0001) after treatment. All psychological measures were significantly improved: DAS 24 (12.1±9.5) (p<0.0001); HADS-anxiety (2.8±3.2) (p<0.0001), HADS-depression (2.0±3.1) (p<0.0001); BFNE (2.9 ± 4.3) (p<0.0001); VAS (3.56±4.1) (p<0.0001). Multiple treatments further improved mouth function (p<0.05), DAS (p<0.0001) and VAS (p = 0.01) scores. SSc fibroblast viability and proliferation was significantly reduced in co-culture compared to monoculture via a paracrine effect over 14 days (p < 0.0001). Protein secretion of transforming growth factor (TGF-ß1) and connective tissue growth factor (CTGF) was significantly reduced in co-culture compared to monoculture (p < 0.0001). Multiple fibrosis associated genes were down regulated in SSc co-culture compared to monoculture after 14 days including Matrix metalloproteinase-8 (MMMP-8), Platelet derived growth factor-ß (PDGF-ß) and Integrin Subunit Beta 6 (ITG-ß6). Autologous stem cell enriched lipotransfer significantly improved the effects of oro-facial fibrosis in SSc in this open cohort study. Lipotransfer may reduce dermal fibrosis through the suppression of fibroblast proliferation and key regulators of fibrogenesis including TG-ß1 and CTGF. Our findings warrant further investigation in a randomised controlled trial.

16.
Ann Rheum Dis ; 78(9): 1242-1248, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31227488

RESUMO

OBJECTIVES: Mortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients with these endpoints, in a population of patients from the European Scleroderma Trials and Research group database. METHODS: Inclusion criteria were diagnosis of diffuse SSc and follow-up over 12±3 months. Disease worsening/organ progression was fulfilled if any of the following events occurred: new renal crisis; decrease of lung or heart function; new echocardiography-suspected pulmonary hypertension or death. In total, 42 clinical parameters were chosen as predictors for the analysis by using (1) imputation of missing data on the basis of multivariate imputation and (2) least absolute shrinkage and selection operator regression. RESULTS: Of 1451 patients meeting the inclusion criteria, 706 had complete data on outcome parameters and were included in the analysis. Of the 42 outcome predictors, eight remained in the final regression model. There was substantial evidence for a strong association between disease progression and age, active digital ulcer (DU), lung fibrosis, muscle weakness and elevated C-reactive protein (CRP) level. Active DU, CRP elevation, lung fibrosis and muscle weakness were also associated with a significantly shorter time to disease progression. A bootstrap validation step with 10 000 repetitions successfully validated the model. CONCLUSIONS: The use of the predictive factors presented here could enable cohort enrichment with patients at risk for overall disease worsening in SSc clinical trials.

17.
18.
Semin Respir Crit Care Med ; 40(2): 184-193, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31137059

RESUMO

Multidisciplinary diagnosis is now viewed as the diagnostic reference standard in interstitial lung disease (ILD). This process consists of the integration of the evidence base with clinical reasoning in the formulation of a diagnosis and requires input from clinicians, radiologists, and, in selected cases, histopathologists. In ILD associated with connective tissue disease (CTD-ILD), multidisciplinary evaluation is especially helpful when CTD is suspected but cannot be diagnosed using strict criteria. In this context, the integration of systemic clinical data, serologic information, and computed tomography and biopsy findings may allow CTD-ILD to be diagnosed. However, the value of multidisciplinary evaluation in CTD-ILD is not confined to diagnosis. The frequent coexistence of pulmonary processes other than ILD, including pulmonary vascular disease, extrapulmonic restriction, and airways disease, often has a major impact on symptoms and pulmonary function tests (PFTs). In this review, we highlight the value of multidisciplinary discussion (MDD) in reconciling clinical data, PFT, and imaging data in the accurate staging of disease severity, baseline prognostic evaluation, and the identification of progression of ILD. MDD also provides a means to combine the views of respiratory physicians and rheumatologists in formulating a treatment strategy. It is often possible to reach a robust view as to whether management should be driven by systemic disease, pulmonary disease, or both. When treatment needs to be introduced or modified for both systemic and pulmonary reasons, face-to-face discussion facilities the selection of therapeutic agents that are likely to be efficacious for both systemic and pulmonary diseases.

19.
Ann Rheum Dis ; 78(5): 648-656, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30852552

RESUMO

OBJECTIVES: To determine whether progressive skin fibrosis is associated with visceral organ progression and mortality during follow-up in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS: We evaluated patients from the European Scleroderma Trials and Research database with dcSSc, baseline modified Rodnan skin score (mRSS) ≥7, valid mRSS at 12±3 months after baseline and ≥1 annual follow-up visit. Progressive skin fibrosis was defined as an increase in mRSS >5 and ≥25% from baseline to 12±3 months. Outcomes were pulmonary, cardiovascular and renal progression, and all-cause death. Associations between skin progression and outcomes were evaluated by Kaplan-Meier survival analysis and multivariable Cox regression. RESULTS: Of 1021 included patients, 78 (7.6%) had progressive skin fibrosis (skin progressors). Median follow-up was 3.4 years. Survival analyses indicated that skin progressors had a significantly higher probability of FVC decline ≥10% (53.6% vs 34.4%; p<0.001) and all-cause death (15.4% vs 7.3%; p=0.003) than non-progressors. These significant associations were also found in subgroup analyses of patients with either low baseline mRSS (≤22/51) or short disease duration (≤15 months). In multivariable analyses, skin progression within 1 year was independently associated with FVC decline ≥10% (HR 1.79, 95% CI 1.20 to 2.65) and all-cause death (HR 2.58, 95% CI 1.31 to 5.09). CONCLUSIONS: Progressive skin fibrosis within 1 year is associated with decline in lung function and worse survival in dcSSc during follow-up. These results confirm mRSS as a surrogate marker in dcSSc, which will be helpful for cohort enrichment in future trials and risk stratification in clinical practice.

20.
Arthritis Res Ther ; 21(1): 81, 2019 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-30917857

RESUMO

Systemic sclerosis (SSc) is an immune-mediated fibrotic disease affecting skin, lung and gut which are all sites with an established microbiome. Altered microbial flora may occur and contribute to the initiation, progression or severity of disease. However, dysbiosis could also be secondary to the disease or immunosuppressive therapy. Here we consider how lessons could be learned from gastroenterology, a speciality where dysbiosis is strongly implicated in disease mechanism and treatment. This could be highly relevant to molecular pathology of skin in SSc and could drive the inflammatory gene signature observed in some skin biopsies.


Assuntos
Microbioma Gastrointestinal , Microbiota , Escleroderma Sistêmico , Disbiose , Humanos , Pele
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