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2.
ACR Open Rheumatol ; 2020 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-33277978

RESUMO

OBJECTIVE: To evaluate short- and long-term outcomes of African American (AA) participants of Scleroderma Lung Studies (SLS) I and II. METHODS: SLS I randomized 158 participants with systemic sclerosis-interstitial lung disease (SSc-ILD) to 1 year of oral cyclophosphamide (CYC) versus placebo. SLS II randomized 142 participants with SSc-ILD to 1 year of oral CYC followed by 1 year of placebo versus 2 years of mycophenolate (MMF). Joint models compared the course of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) between AA and non-AA, and Cox proportional hazard models assessed long-term morbidity and mortality outcomes. RESULTS: In SLS I, there was no difference in the course of the FVC or DLCO between AA and non-AA in either treatment arm. In SLS II, AA had an improved course of the FVC compared with non-AA in the CYC arm; in the MMF arm, there was no difference in FVC course. There was no difference in DLCO course in either arm. Time to death and respiratory failure were similar for AA and non-AA in SLS I. There was a trend for improved survival and time to respiratory failure in AA compared with non-AA in SLS II. AA race was not independently associated with mortality in the SLS I or II in the Cox models. CONCLUSION: Data from two randomized controlled trials demonstrated that AA patients with SSc-ILD have similar morbidity and mortality outcomes compared with non-AA patients. These findings contrast with the racial disparities described in prior observational studies and warrant further investigation.

4.
Arthritis Rheumatol ; 2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33350170

RESUMO

OBJECTIVE: Response to immunosuppression is highly variable in systemic sclerosis (SSc) related interstitial lung disease (ILD). We hypothesized that a composite serum Interferon Inducible Serum Protein Score would exhibit predictive significance for the response to immunosuppression in SSc-ILD. METHODS: Serum samples collected in the Scleroderma Lung Study II, a randomized controlled trial of mycophenolate versus cyclophosphamide, were examined. Results were validated in an independent observational cohort on active treatment. A composite score of 6 interferon inducible proteins (IP-10, MIG, MCP-2, B2M, TNFR2, and MIP-3 beta) was calculated and its predictive significance for longitudinal forced vital capacity % predicted measurements was examined. RESULTS: Higher baseline Interferon Inducible Protein Score predicted better response over 3 to 12-month visits in the mycophenolate (b=0.41, p=0.001) and cyclophosphamide (b=0.91, p=0.009) arms. In contrast, higher baseline c-reactive protein (CRP) levels predicted worse ILD course in both treatment arms. The predictive significance of Interferon Inducible Protein Score and CRP remained after adjustment for baseline demographic/clinical predictors. During the second-year placebo treatment period of the cyclophosphamide arm, higher Interferon Inducible Protein Score at 12 months showed a trend for predicting worse ILD course (b=-0.61, p=0.068) while it continued predicting better response to active immunosuppression in the mycophenolate arm (b=0.28, p=0.029). The predictive significance of baseline Interferon Inducible Protein Score was replicated in the independent cohort (rs =0.43; p=0.028). CONCLUSIONS: Higher Interferon Inducible Protein Score in SSc-ILD predicts better response to immunosuppression and could be potentially used for identifying patients who may derive the most benefit from these two treatments.

5.
Arthritis Rheumatol ; 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33142016

RESUMO

OBJECTIVE: In the SENSCIS trial in subjects with systemic sclerosis-associated ILD (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) over 52 weeks by 44% versus placebo. We investigated the effects of nintedanib on categorical changes in FVC and other measures of ILD progression. METHODS: In post-hoc analyses, we assessed the proportions of subjects with categorical changes in FVC % predicted at week 52 and the time to absolute decline in FVC ≥5% predicted or death and absolute decline in FVC ≥10% predicted or death. RESULTS: A total of 288 subjects received nintedanib and 288 received placebo. At week 52, in subjects treated with nintedanib and placebo, respectively, 55.7% and 66.3% had any decline in FVC % predicted, 13.6% and 20.1% had an FVC decline >5%-≤10% predicted, and 3.5% and 5.2% had an FVC decline >10%-≤15% predicted; 34.5% and 43.8% had a decrease in FVC ≥3.3% predicted (proposed minimal clinically important difference [MCID] for worsening of FVC), while 23.0% and 14.9% had an increase in FVC ≥3.0% predicted (proposed MCID for improvement in FVC). Over 52 weeks, the hazard ratio for an absolute decline in FVC ≥5% predicted or death with nintedanib versus placebo was 0.83 (95% CI: 0.66, 1.06) (P=0.14) and the hazard ratio for an absolute decline in FVC ≥10% predicted was 0.64 (95% CI: 0.43, 0.95); P=0.029. CONCLUSION: These results suggest that nintedanib has a clinically relevant benefit on the progression of SSc-ILD.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33064934

RESUMO

OBJECTIVE: Scleroderma (SSc)-associated gastrointestinal (GI) complications are attributed to a variety of factors including diet, microbiota dysbiosis, or GI transit abnormalities. We examined the contribution of abnormal GI transit to SSc Medsger GI severity scores and/or UCLA GIT 2.0 symptoms. METHODS: Patients with SSc and GI symptoms (n=71) and healthy controls (n=18) underwent whole gut transit (WGT) scintigraphy to assess transit from the esophagus to the colon. The presence of delayed transit and percent emptying in each GI region were measured. We compared the WGT measurements between categories of the Medsger GI severity score (0-4) and across UCLA GIT 2.0 domains and total score (0-3). RESULTS: Eighty-percent of patients had >1 abnormal region of the gut on WGT scintigraphy. All patients requiring total parenteral nutrition had delayed small bowel transit, compared to only ~11% of patients in other Medsger GI severity groups (p=<0.01). Severe colonic transit delays were more likely in patients with Medsger GI scores of 3 (pseudo-obstruction and/or malabsorption) compared to other Medsger GI groups (p=0.02). Seventy-percent of these patients had ≤30% colonic emptying at 72 hours. Modest associations were noted between GERD symptoms and delayed esophageal (r=-0.31,p=0.05) and gastric emptying (r=-0.32,p=0.05). CONCLUSION: These data are important in providing evidence that SSc bowel disease affects transit of GI content and that delay in transit accounts in part for both bowel symptoms and Medsger GI severity. Prospective studies examining the benefit of early therapeutic intervention targeting GI transit abnormalities in patients at high-risk for severe GI complications are needed.

7.
J Rheumatol ; 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934125

RESUMO

Infection with the coronavirus disease 2019 (Covid-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), manifests in a myriad of ways ranging from asymptomatic disease to pneumonia and acute respiratory distress syndrome. Advanced age and underlying cardiovascular/pulmonary conditions appear to increase the risk for Covid-19 complications [1,2]. Patients with connective tissue disease-related interstitial lung disease (CTD-ILD) may represent a vulnerable patient population for Covid-19 given their diminished pulmonary reserve. To our knowledge, there are no prospective data reporting outcomes of SARS-CoV-2 infection in patients with CTD-ILD. We herein present all known cases (n = 4) of Covid-19 in CTD-ILD patients at UCLA between January 2020 and August 2020.

8.
Semin Arthritis Rheum ; 50(5): 963-967, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32906032

RESUMO

OBJECTIVE: To investigate the prevalence of the MUC5B promoter variant rs35705950 in patients with systemic sclerosis-interstitial lung disease (SSc-ILD) and whether its presence predicts response to immunosuppression with cyclophosphamide (CYC) and mycophenolate (MMF). METHODS: SSc-ILD patients who participated in Scleroderma Lung Study (SLS) II (MMF versus CYC) were included in this study (N = 142). TaqMan Genotyping Assays were used to determine the MUC5B rs35705950 single nucleotide polymorphism. Joint models were created to examine how the presence of this variant affected the course of the forced vital capacity (FVC) over 2 years. Linear regression models were used to investigate the relationship between the presence of this variant and the change in quantitative radiographic fibrosis. RESULTS: Among 128 participants who were tested for this variant, 18% possessed at least one copy of the MUC5B minor allele. Patients with at least one copy of this allele were similar to those without the allele with respect to age, sex, SSc subtype, ILD disease severity; however, this variant was rare among African Americans (3.7%). The presence of the MUC5B variant did not affect the course of the FVC, nor the change in quantitative radiographic fibrosis, ground glass or ILD scores in either treatment arm. CONCLUSION: In the context of a randomized controlled trial for SSc-ILD, the presence of the MUC5B variant did not predict disease severity, nor affect treatment response to MMF or CYC. Future studies are needed to determine whether this variant affects ILD progression in other SSc cohorts and in patients receiving anti-fibrotic therapy.

9.
Expert Opin Pharmacother ; 21(16): 2041-2056, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32674612

RESUMO

INTRODUCTION: Systemic sclerosis (SSc) is a multi-dimensional connective tissue disease of unknown etiology. Given the immense clinical complexity of SSc, the treatment of this condition is not standardized and considerable heterogeneity exists in SSc management approaches. The purpose of this article is to highlight novel therapeutic strategies and new medications under development for the treatment of systemic sclerosis (SSc). AREAS COVERED: Herein, the authors focus primarily on recently completed clinical trials and phase 3 and 4 clinical trials of therapeutic agents that show promise in SSc. This review is organized by the clinical complications that occur in SSc, for which novel treatment strategies are under study. EXPERT OPINION: Combining therapies to address the individual manifestations of SSc is a cornerstone to the comprehensive management of this condition. Therapeutic strategies must take into account the organs involved, the level of disease activity in each area, and the disease stage. Controlling the complex biological network, progressive vasculopathy and fibrosis, as well as manifestations of end-organ dysfunction are all critical considerations when determining the best treatment approach for SSc.

10.
Lancet ; 396(10246): 218-219, 2020 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-32711782
11.
ACR Open Rheumatol ; 2(6): 362-370, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32432411

RESUMO

OBJECTIVE: Our objective was to determine if treatment with cyclophosphamide (CYC) and mycophenolate mofetil (MMF) improves patient-reported outcomes (PROs) among patients with systemic sclerosis-related interstitial lung disease (SSc-ILD). METHODS: This study examined PROs in patients with SSc-ILD (N = 142) who participated in the Scleroderma Lung Study II, a randomized controlled trial comparing MMF for 2 years with oral CYC for 1 year followed by 1 year of a placebo. Joint models were created to evaluate the course of PROs over 2 years. The difference in PRO scores from baseline to 24 months was measured, and the percentage of patients meeting the minimum clinically important difference (MCID) was calculated. Correlations between PROs and SSc-ILD disease severity measures were also examined. RESULTS: Treatment with CYC and MMF led to improvements in several PROs with no between-treatment differences. Scores for the Transitional Dyspnea Index (TDI) and St. George's Respiratory Questionnaire (SGRQ) improved significantly over 2 years, and 29%/24% and 28%/25% of participants in the CYC/MMF groups met or exceeded the MCID estimates for TDI and SGRQ, respectively. At baseline, the forced vital capacity (FVC) percentage predicted (FVC%-predicted) did not correlate with the Baseline Dyspnea Index or SGRQ. However, improvements in the FVC%-predicted were weakly associated with improvements in dyspnea (assessed by the TDI) and SGRQ scores. CONCLUSION: Treatment with CYC and MMF improved overall health-related quality of life in patients with SSc-ILD. The relationship between PRO measures and the FVC was relatively weak, suggesting that PROs provide complementary information about treatment efficacy not captured by changes in the FVC alone in this patient population.

12.
Eur Respir J ; 55(5)2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32079645

RESUMO

Systemic sclerosis (SSc) is a systemic autoimmune disease affecting multiple organ systems, including the lungs. Interstitial lung disease (ILD) is the leading cause of death in SSc.There are no valid biomarkers to predict the occurrence of SSc-ILD, although auto-antibodies against anti-topoisomerase I and several inflammatory markers are candidate biomarkers that need further evaluation. Chest auscultation, presence of shortness of breath and pulmonary function testing are important diagnostic tools, but lack sensitivity to detect early ILD. Baseline screening with high-resolution computed tomography (HRCT) is therefore necessary to confirm an SSc-ILD diagnosis. Once diagnosed with SSc-ILD, patients' clinical courses are variable and difficult to predict, although certain patient characteristics and biomarkers are associated with disease progression. It is important to monitor patients with SSc-ILD for signs of disease progression, although there is no consensus about which diagnostic tools to use or how often monitoring should occur. In this article, we review methods used to define and predict disease progression in SSc-ILD.There is no valid definition of SSc-ILD disease progression, but we suggest that either a decline in forced vital capacity (FVC) from baseline of ≥10%, or a decline in FVC of 5-9% in association with a decline in diffusing capacity of the lung for carbon monoxide of ≥15% represents progression. An increase in the radiographic extent of ILD on HRCT imaging would also signify progression. A time period of 1-2 years is generally used for this definition, but a decline over a longer time period may also reflect clinically relevant disease progression.

13.
Eur J Rheumatol ; 7(Suppl 3): S228-S236, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31922474

RESUMO

Systemic sclerosis (SSc) is a complex autoimmune disease of unknown etiology. Genetic factors are thought to collude with various environmental triggers to induce SSc and subsequently manifest various SSc disease phenotypes. Emerging evidence suggests that the microbiota of the gastrointestinal tract (GIT) may represent a key pathogenic participant in this disease state. Recent studies have demonstrated specific alterations in the GIT microbial composition in SSc patients, and this article reviews studies that have investigated the GIT microbiota in SSc patients. The focus of this article is to highlight the modifications in the GIT microbiota observed in SSc patients belonging to different cohorts and to demonstrate how these alterations may be associated with specific SSc features. This article presents the results of these SSc microbiota studies in the context of findings from microbiotic studies in other autoimmune states to explore similarities and differences across disease states affecting the immune system. Finally, this article provides insights into potential SSc therapies that target the GIT microbiota. Given the complexity and variability of the SSc disease state, any treatment aimed at modulating GIT microbiota will likely need to be coupled with additional interventions that target other SSc disease components.

14.
Arthritis Rheumatol ; 72(2): 316-325, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31430058

RESUMO

OBJECTIVE: To examine changes in the extent of specific patterns of interstitial lung disease (ILD) as they transition from one pattern to another in response to immunosuppressive therapy in systemic sclerosis-related ILD (SSc-ILD). METHODS: We evaluated changes in the quantitative extent of specific lung patterns of ILD using volumetric high-resolution computed tomography (HRCT) scans obtained at baseline and after 2 years of therapy in patients treated with either cyclophosphamide (CYC) for 1 year or mycophenolate mofetil (MMF) for 2 years in Scleroderma Lung Study II. ILD patterns included lung fibrosis, ground glass, honeycombing, and normal lung. Net change was calculated as the difference in the probability of change from one ILD pattern to another. Wilcoxon's signed rank test was used to compare the changes. RESULTS: Forty-seven and 50 patients had baseline and follow-up scans in the CYC and MMF groups, respectively. Mean net improvements reflecting favorable changes from one ILD pattern to another in the whole lung in the CYC and MMF groups, respectively, were as follows: from lung fibrosis to a normal lung pattern, 21% and 19%; from a ground-glass pattern to a normal lung pattern, 30% and 28%; and from lung fibrosis to a ground-glass pattern, 5% and 0.5%. The mean overall improvement in transitioning from a ground-glass pattern or lung fibrosis to a normal lung pattern was significant for both treatments (all P < 0.001). CONCLUSION: Significantly favorable transitions from both ground-glass and lung fibrosis ILD patterns to a normal lung pattern were observed in patients undergoing immunosuppressive treatment for SSc-ILD, suggesting the usefulness of examining these transitions for insights into the underlying pathobiology of treatment response.


Assuntos
Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/tratamento farmacológico , Ácido Micofenólico/uso terapêutico , Tomografia Computadorizada por Raios X/métodos , Adulto , Feminino , Humanos , Doenças Pulmonares Intersticiais/etiologia , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/complicações , Resultado do Tratamento
15.
Open Access Rheumatol ; 11: 283-307, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31849543

RESUMO

Systemic sclerosis (SSc) is a progressive and often devastating disease characterized by autoimmune dysfunction, vasculopathy, and fibrosis. Interstitial lung disease (ILD) is identified in the majority of patients with SSc and is the leading cause of SSc-related mortality. Although clinical manifestations and ILD severity vary among patients, lung function typically declines to the greatest extent during the first 3-4 years after disease onset. We aim to provide an overview of SSc-associated ILD (SSc-ILD) with a focus on current and emerging tools for early diagnosis of ILD and current and novel treatments under investigation. Early detection of ILD provides the opportunity for early therapeutic intervention, which could improve patient outcomes. Thoracic high-resolution computed tomography is the most effective method of identifying ILD in patients with SSc; it enables detection of mild lung abnormalities and plays an important role in monitoring disease progression. Cyclophosphamide and mycophenolate mofetil are the most commonly prescribed treatments for SSc-ILD. Recently, nintedanib (an antifibrotic) was approved by the Food and Drug Administration for patients with SSc-ILD; it is indicated for slowing the rate of decline in pulmonary function. However, there is a need for additional effective and well-tolerated disease-modifying therapy. Ongoing studies are evaluating other antifibrotics and novel agents. We envision that early detection of lung involvement, combined with the emergence and integration of novel therapies, will lead to improved outcomes in patients with SSc-ILD.

16.
EBioMedicine ; 50: 379-386, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31732480

RESUMO

BACKGROUND: Some interstitial lung disease (ILD) patients develop a progressive fibrosing-ILD phenotype (PF-ILD), with similar persistent lung function decline suggesting common molecular pathways involved. Nintedanib, a tyrosine kinase inhibitor targeting the PDGF, FGF, VEGF and M-CSF pathways, has shown comparable efficacy in idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated ILD (SSc-ILD). We hypothesize that Nintedanib targeted molecular pathways will be augmented to a similar degree across PF-ILD regardless of aetiology. METHODS: We collected explanted lung tissue at the time of lung transplantation from 130 PF-ILD patients (99 (76%) IPF, 14 (11%) SSc-ILD, 17 (13%) other PF-ILD), and wedge biopsies from 200 donor lungs and measured PDGF, FGF, VEGF and M-CSF concentrations by Luminex. FINDINGS: The concentrations of PDGF-AA, PDGF-BB, FGF-2, VEGF and M-CSF were significantly increased in PF-ILD lungs compared to donor lungs (PDGF-AA 93·0 pg/ml [±97·2] vs. 37·5 pg/ml [±35·4], p < 0·001; PDGF-BB 102·5 pg/ml [±78·8] vs. 61·9 pg/ml [±47·0], p < 0·001; FGF-2 1442·4 pg/ml [±426·6] vs. 1201·7 pg/ml [±535·2], p = 0·009; VEGF 40·6 pg/ml [±20·1] vs. 24·9 pg/ml [±29·5], p < 0·001; and M-CSF 25526 pg/ml [±24,799] vs. 6120 pg/ml [±7245], p < 0·001). There were no significant differences in these growth factor/angiogenic molecules/cytokine concentrations when segregated by IPF, SSc-ILD and other PF-ILDs. INTERPRETATION: Nintedanib specific targeted molecular pathways are augmented to a similar magnitude in all PF-ILD lung tissue as compared to controls, suggesting that Nintedanib treatment may be efficacious in PF-ILD regardless of aetiology. We speculate that clinical trials using Nintedanib for PF-ILD with or without IPF or SSc-ILD should show a similar relative reduction in FVC decline as seen in IPF and SSc-ILD (∼45-50%). FUNDING: Health Grant P01-HL108793 (JAB), South-Eastern Norway Regional Health Authority Grant 2018072 (AMHV).


Assuntos
Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/patologia , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/patologia , Fenótipo , Idoso , Biomarcadores , Citocinas/metabolismo , Progressão da Doença , Suscetibilidade a Doenças , Feminino , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/terapia , Mediadores da Inflamação/metabolismo , Doenças Pulmonares Intersticiais/metabolismo , Masculino , Pessoa de Meia-Idade
17.
Expert Rev Clin Immunol ; 15(10): 1009-1017, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31566449

RESUMO

Introduction: Systemic sclerosis (SSc) is a rare and complex connective tissue disease characterized by fibrosis of the skin and internal organs. Interstitial lung disease (ILD) is a common complication of SSc and the leading cause of SSc-related death. No drugs are licensed for the treatment of SSc-ILD. Areas covered: This review provides an overview of the current treatment of SSc-ILD and a perspective on investigational therapies, focusing on those studied in randomized controlled trials. Expert opinion: There is substantial room for improvement in the treatment of SSc-ILD. Current treatment focuses on immunosuppressant therapies, particularly cyclophosphamide and mycophenolate. Hematopoietic stem cell transplantation has been shown to improve long-term outcomes, but the risk of treatment-related mortality restricts its use to select patients at specialized centers. Modifying the course of disease to improve outcomes remains the goal for new therapies. Several drugs are under investigation as potential therapies for SSc-ILD, providing hope that the limited treatment armamentarium for SSc-ILD will be expanded and improved in the near future. Expert consensus is needed on how to screen for and monitor SSc-ILD and on when to initiate and escalate therapy.


Assuntos
Doenças Pulmonares Intersticiais/terapia , Escleroderma Sistêmico/complicações , Anticorpos Monoclonais Humanizados/uso terapêutico , Ciclofosfamida/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Indóis/uso terapêutico , Transplante de Pulmão , Piridonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Rituximab/uso terapêutico , Transplante Autólogo
18.
Arthritis Rheumatol ; 71(12): 2059-2067, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31233287

RESUMO

OBJECTIVE: To investigate the relationship between Krebs von den Lungen 6 (KL-6) and CCL18 levels and the severity and progression of systemic sclerosis (SSc)-related interstitial lung disease (ILD). METHODS: Patients enrolled in the Scleroderma Lung Study II (cyclophosphamide [CYC] versus mycophenolate mofetil [MMF]) were included. Baseline and 12-month plasma samples were analyzed by enzyme-linked immunosorbent assay to assess CCL18 and KL-6 levels. The forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLco) were measured every 3 months. Joint models were created to investigate the relationship between baseline CCL18 and KL-6 levels and the course of the FVC and DLco over 1 year according to treatment arm. RESULTS: Baseline KL-6 and CCL18 levels each correlated with the extent of radiographic fibrosis. Levels of both CCL18 and KL-6 declined significantly at 1 year. In both treatment arms (n = 71 for CYC, n = 62 for MMF), a higher baseline KL-6 level predicted progression of ILD based on the course of FVC (P = 0.024 for CYC; P = 0.005 for MMF) and DLco (P < 0.001 for CYC; P = 0.004 for MMF) over 1 year. A higher baseline CCL18 level predicted progression of ILD based on the course of the FVC (P < 0.001 for CYC; P = 0.007 for MMF) and DLco (P = 0.001 for CYC; P < 0.001 for MMF) over 1 year, as well as mortality (P = 0.0008 for CYC arm only). CONCLUSION: In a rigorously conducted clinical trial for SSc-related ILD, KL-6 and CCL18 levels correlated with ILD severity and declined with immunosuppression. Patients with higher baseline KL-6 and CCL18 levels were more likely to experience disease progression despite treatment. KL-6 and CCL18 levels could be used to identify patients with a progressive ILD phenotype who may benefit from a more aggressive initial treatment approach.


Assuntos
Quimiocinas CC/metabolismo , Doenças Pulmonares Intersticiais/fisiopatologia , Mucina-1/metabolismo , Escleroderma Sistêmico/genética , Adolescente , Adulto , Idoso , Ciclofosfamida/uso terapêutico , Progressão da Doença , Feminino , Humanos , Imunossupressores/uso terapêutico , Pulmão/metabolismo , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/genética , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Testes de Função Respiratória , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Capacidade Vital , Adulto Jovem
19.
Nat Rev Rheumatol ; 15(4): 208-224, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30796362

RESUMO

Systemic sclerosis (SSc) has the highest cause-specific mortality of all the connective tissue diseases, and the aetiology of this complex and heterogeneous condition remains an enigma. Current disease-modifying therapies for SSc predominantly target inflammatory and vascular pathways but have variable and unpredictable clinical efficacy, and none is curative. Moreover, many of these therapies possess undesirable safety profiles and have no appreciable effect on long-term mortality. This Review describes the most promising of the existing therapeutic targets for SSc and places them in the context of our evolving understanding of the pathophysiology of this disease. As well as taking an in-depth look at the immune, inflammatory, vascular and fibrotic pathways implicated in the pathogenesis of SSc, this Review discusses emerging treatment targets and therapeutic strategies. The article concludes with an overview of important unanswered questions in SSc research that might inform the design of future studies of treatments aimed at modifying the course of this disease.


Assuntos
Escleroderma Sistêmico/terapia , Humanos , Terapia de Alvo Molecular/métodos , Escleroderma Sistêmico/imunologia
20.
J Rheumatol ; 46(10): 1316-1325, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30770517

RESUMO

OBJECTIVE: To compare safety and efficacy outcomes between the cyclophosphamide (CYC) arms of Scleroderma Lung Study (SLS) I and II. METHODS: Participants enrolled in the CYC arms of SLS I (n = 79) and II (n = 69) were included. SLS I and II randomized participants to oral CYC for 1 year and followed patients for an additional year off therapy (in SLS II, patients received placebo in Year 2). Eligibility criteria for SLS I and II were nearly identical. Outcomes included the forced vital capacity (FVC%)-predicted and DLCO%-predicted (measured every 3 mos) and quantitative radiographic extent of interstitial lung disease (measured at 1 and 2 yrs for SLS I and SLS II, respectively). Joint models were created to evaluate the treatment effect on the course of the FVC/DLCO over 2 years while controlling for baseline disease severity. RESULTS: SLS I and II CYC participants had similar baseline characteristics. After adjusting for baseline disease severity, there was no difference in the course of the FVC%-predicted (p = 0.535) nor the DLCO%-predicted (p = 0.172) between the SLS I and II CYC arms. In both groups, treatment with CYC led to a significant improvement in the FVC%-predicted from 3 to 12 months, but no significant improvement beyond this point. Treatment with CYC had no effect on the DLCO for either group. CONCLUSION: Treatment with 1 year of oral CYC led to similar improvements in lung function in both SLS I and II, although the effects were not sustained following cessation of CYC. These results suggest that increasing the duration of ILD therapy may improve outcomes for patients with systemic sclerosis-ILD.


Assuntos
Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/tratamento farmacológico , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Ciclofosfamida/efeitos adversos , Feminino , Seguimentos , Humanos , Imunossupressores/efeitos adversos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Capacidade de Difusão Pulmonar/efeitos dos fármacos , Resultado do Tratamento , Capacidade Vital/efeitos dos fármacos
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