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2.
Ann Rheum Dis ; 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568386

RESUMO

BACKGROUND/OBJECTIVES: The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 classification criteria for systemic lupus erythematosus system showed high specificity, while attaining also high sensitivity. We hereby analysed the performance of the individual criteria items and their contribution to the overall performance of the criteria. METHODS: We combined the EULAR/ACR derivation and validation cohorts for a total of 1197 systemic lupus erythematosus (SLE) and n=1074 non-SLE patients with a variety of conditions mimicking SLE, such as other autoimmune diseases, and calculated the sensitivity and specificity for antinuclear antibodies (ANA) and the 23 specific criteria items. We also tested performance omitting the EULAR/ACR criteria attribution rule, which defines that items are only counted if not more likely explained by a cause other than SLE. RESULTS: Positive ANA, the new entry criterion, was 99.5% sensitive, but only 19.4% specific, against a non-SLE population that included other inflammatory rheumatic, infectious, malignant and metabolic diseases. The specific criteria items were highly variable in sensitivity (from 0.42% for delirium and 1.84% for psychosis to 75.6% for antibodies to double-stranded DNA), but their specificity was uniformly high, with low C3 or C4 (83.0%) and leucopenia <4.000/mm³ (83.8%) at the lowest end. Unexplained fever was 95.3% specific in this cohort. Applying the attribution rule improved specificity, particularly for joint involvement. CONCLUSIONS: Changing the position of the highly sensitive, non-specific ANA to an entry criterion and the attribution rule resulted in a specificity of >80% for all items, explaining the higher overall specificity of the criteria set.

3.
Arthritis Rheumatol ; 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33538058

RESUMO

OBJECTIVE: Data on the magnitude of benefit of modern pulmonary arterial hypertension (PAH) therapies in connective tissue disease-associated PAH (CTD-PAH) are limited. We performed meta-analyses of randomized, controlled trials (RCTs) and registries to quantify this benefit (PROSPERO# CRD42020167119). METHODS: PubMed and EMBASE were searched for articles reporting data from RCTs or registries published 1/1/2000-11/25/2019. Eligibility criteria included multicenter studies with ≥30 CTD-PAH patients. RCTs had to evaluate approved PAH therapy and report long-term clinical morbidity/mortality or 6-minute walk distance. Registries had to report survival. Random effects models were used to pool data. RESULTS: Eleven RCTs (N=4329 n=1267 CTD-PAH) and 19 registries (N=9739; n=4008 CTD-PAH) were included. Investigational therapy produced a 36% reduction in risk of clinical morbidity/mortality events versus control (HR=0.64; 95%CI: 0.54-0.75; P<0.001) in all patients and a 36% reduction (HR=0.64; 95% CI: 0.51-0.81; P<0.001) in CTD-PAH patients. Survival was lower in CTD-PAH versus all patients (62%, 95% CI: 57%-67% versus 72%, 95% CI: 69%-75% at 3 years). Survival in CTD-PAH patients treated primarily after 2010 was higher than in those treated before (73%, 95% CI: 62%-81% versus 65%, 95% CI: 59%-71% at 3 years). CONCLUSIONS: Modern therapy provides a similar reduction in morbidity/mortality risk in CTD-PAH and the overall PAH population. Risk of death is higher in CTD-PAH than in PAH overall, but survival has improved in the last 10 years, which may be related to increased screening and/or new treatment approaches. Early detection of PAH in patients with CTD and upfront intensive treatment are warranted.

4.
Arthritis Rheumatol ; 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33538094

RESUMO

OBJECTIVE: Tocilizumab has demonstrated lung function preservation in two randomized controlled trials in early systemic sclerosis (SSc). This effect has yet to be characterized in terms of quantitative radiographic lung involvement. In this post-hoc analysis, we assess tocilizumab's impact on lung function preservation, stratifying treatment arms by the degree of radiographic lung involvement. METHODS: The focuSSced trial was a phase 3, randomized placebo-controlled trial of tocilizumab in patients with SSc and progressive skin disease. Participants had baseline and serial spirometry along with high resolution chest CT at baseline and week 48. Quantitative interstitial lung disease and fibrosis were derived using computer software. We divided quantitative interstitial lung disease in mild (5-10%), moderate (>10-20%), or severe (>20%) categories. RESULTS: Of 210 participants recruited in the trial, 136 [65%] had interstitial lung disease. The majority of these participants had moderate-to-severe involvement defined by >10% lung involvement (77%). The tocilizumab arm demonstrated preservation of forced vital capacity over 48 weeks (least squared mean change in %predicted = -0.1) compared to placebo (-6.3%). For mild, moderate, and severe QILD, the mean decline in the %pFVC in the tocilizumab arm at 48 weeks were -4.1, 0.7, and 2.1, and in the placebo group were -10.0, -5.7, and -6.7, respectively. Similar treatment-related preservation findings were seen independent of fibrosis severity. CONCLUSION: Tocilizumab in early SSc- associated interstitial lung disease with progressive skin disease stabilized forced vital capacity over 48 weeks, independent of the extent of quantitative radiographic interstitial lung disease or fibrosis.

5.
Arthritis Rheumatol ; 2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33586346

RESUMO

OBJECTIVE: Systemic sclerosis (SSc) is characterized by widespread fibrosis and vascular complications. In this study, we utilized an assay for genome-wide chromatin accessibility to examine the chromatin landscape and transcription factor footprints in SSc. METHODS: Dermal endothelial cells (ECs) and fibroblasts were isolated from healthy controls and patients with diffuse cutaneous (dc) SSc. ATAC-seq was performed to assess genome-wide chromatin accessibility at a read depth of approximately 150 million reads/sample. Transcription factor footprinting and motif binding analysis was performed followed by functional experiments. RESULTS: Chromatin accessibility was significantly reduced in dcSSc patients compared to healthy controls. Differentially accessible chromatin loci were enriched in pathways and gene ontologies involved in the nervous system, cell membrane projections and cilia motility, nuclear and steroid receptors, and nitric oxide. In addition, chromatin binding of transcription factors SNAI2, ETV2, and ELF1 was significantly increased in dcSSc ECs, while recruitment of RUNX1 and RUNX2 was enriched in dcSSc fibroblasts. We revealed significant downregulation of the neuronal gene NRXN1 and upregulation of SNAI2 and ETV2 in dcSSc ECs. In dcSSc fibroblasts, downregulation of neuronal gene ENTPD1 and upregulation of RUNX2 were confirmed. Further functional analysis revealed that ETV2 and NRXN1 dysregulation affected angiogenesis in ECs, while ENTPD1 enhanced pro-fibrotic properties in dcSSc fibroblasts. CONCLUSION: Our data uncovered the chromatin blueprint of dcSSc, and suggested that neuronal-related characteristics of SSc ECs and fibroblasts could be a culprit for dysregulated angiogenesis and enhanced fibrosis. Targeting key pathways and transcription factors identified might present novel therapeutic approaches in SSc.

6.
J Rheumatol ; 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33452163

RESUMO

OBJECTIVE: The University of California Los Angeles Scleroderma Clinical Trials Consortium gastrointestinal tract 2.0 (UCLA GIT 2.0) questionnaire is a self-reported tool measuring gastrointestinal (GI) quality of life in systemic sclerosis (SSc) patients. Scarce data are available on the correlation between patient reported GI symptoms and motility dysfunction as assessed by esophageal transit scintigraphy. METHODS: We evaluated the UCLA GIT 2.0 reflux scale in SSc patients admitted to our clinic and undergoing esophageal transit scintigraphy, and correlated their findings. RESULTS: Thirty-one SSc patients undergoing esophageal transit scintigraphy were included. Twentyseven were female, 8 with diffuse cutaneous subset; 26/31 (84%) patients had a delayed transit and an abnormal esophageal emptying activity. Mean (SD) emptying activity percentage was higher in patients with none-to-mild GIT 2.0 reflux score [81.1 (11.5)] than in those with the moderate [55.7 (17.8), p = 0.003] and severe-to-very-severe scores [55.8 (19.7), p = 0.002]. The 26 (84%) SSc patients with delayed esophageal transit had a higher GIT 2.0 reflux score (p=0.04). Percentage of esophageal emptying activity negatively correlated with the GIT 2.0 reflux score (r = - 0.68, p < 0.0001) while it did not correlate with the other scales and the total GIT 2.0 score. CONCLUSION: SSc patients with impaired esophageal scintigraphy findings have a higher GIT 2.0 reflux score. The UCLA SCTC GIT 2.0 is a complementary tool for objective measurement of esophageal involvement which can be easily administered in day-to-day clinical assessment.

7.
Lancet Respir Med ; 9(1): 96-106, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33412120

RESUMO

BACKGROUND: In the Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) trial, nintedanib reduced the rate of decline in forced vital capacity (FVC) in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). Patients on stable treatment with mycophenolate for at least 6 months before randomisation could participate. The aim of this subgroup analysis was to examine the efficacy and safety of nintedanib by mycophenolate use at baseline. METHODS: The SENSCIS trial was a randomised, double-blind, placebo-controlled trial, in which patients with SSc-ILD were randomly assigned (1:1) to receive 150 mg of oral nintedanib twice daily or placebo for at least 52 weeks. In a prespecified subgroup analysis, we analysed the primary endpoint of rate of decline in FVC over 52 weeks by mycophenolate use at baseline. In a post-hoc analysis, we analysed the proportion of patients with an absolute decrease in FVC of at least 3·3% predicted at week 52 (proposed minimal clinically important difference estimate for worsening of FVC in patients with SSc-ILD) in subgroups by mycophenolate use at baseline. Adverse events were reported in subgroups by mycophenolate use at baseline. Analyses were done in all participants who received at least one dose of study drug. We analysed the annual rate of decline in FVC using a random coefficient regression model (with random slopes and intercepts) including anti-topoisomerase I antibody status, age, height, sex, and baseline FVC as covariates and terms for baseline-by-time, treatment-by-subgroup, and treatment-by-subgroup-by-time interactions. SENSCIS is registered with ClinicalTrials.gov, NCT02597933, and is now complete. FINDINGS: Between Nov 30, 2015, and Oct 31, 2017, 819 participants were screened and 576 were enrolled, randomly assigned to, and treated with nintedanib (n=288) or placebo (n=288). 139 (48%) of 288 in the nintedanib group and 140 (49%) of 288 in the placebo group were taking mycophenolate at baseline. In patients taking mycophenolate at baseline, the adjusted mean annual rate of decline in FVC was -40·2 mL per year (SE 19·8) with nintedanib and -66·5 mL per year (19·3) with placebo (difference: 26·3 mL per year [95% CI -27·9 to 80·6]). In patients not taking mycophenolate at baseline, the adjusted mean annual rate of decline in FVC was -63·9 mL per year (SE 19·3) with nintedanib and -119·3 mL per year (19·0) with placebo (difference: 55·4 mL per year [95% CI 2·3 to 108·5]). We found no heterogeneity in the effect of nintedanib versus placebo on the annual rate of decline in FVC between the subgroups by mycophenolate use (p value for interaction=0·45). In a post-hoc analysis, the proportion of patients with an absolute decrease in FVC of at least 3·3% predicted was lower with nintedanib than with placebo in both patients taking mycophenolate (40 [29%] of 138 vs 56 [40%] of 140; odds ratio 0·61 [0·37 to 1·01]) and those not taking mycophenolate (59 [40%] of 149 vs 70 [47%] of 148; 0·73 [0·46 to 1·16]) at baseline. The adverse event profile of nintedanib was similar between the subgroups. Diarrhoea, the most common adverse event, was reported in 106 (76%) of 139 patients in the nintedanib group and 48 (34%) of 140 in the placebo group among those taking mycophenolate at baseline, and in 112 (75%) of 149 in the nintedanib group and 43 (29%) of 148 in the placebo group among those not taking mycophenolate at baseline. Over the entire trial period, 19 patients died (ten in the nintedanib group and nine in the placebo group). One death in the nintedanib group was considered to be related to study drug. INTERPRETATION: Nintedanib reduced the progression of interstitial lung disease both in patients with SSc-ILD who were and were not using mycophenolate at baseline, with no heterogeneity in its treatment effect detected between the subgroups. The adverse event profile of nintedanib was similar in the subgroups by mycophenolate use. Our findings suggest that the combination of mycophenolate and nintedanib offers a safe treatment option for patients with SSc-ILD. More data are needed on the benefits of initial combination therapy versus a sequential approach to treatment of SSc-ILD. FUNDING: Boehringer Ingelheim.


Assuntos
Indóis/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Ácido Micofenólico/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Escleroderma Sistêmico/tratamento farmacológico , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Indóis/efeitos adversos , Doenças Pulmonares Intersticiais/etiologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Escleroderma Sistêmico/complicações , Resultado do Tratamento
8.
Clin Rheumatol ; 2021 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-33486597

RESUMO

INTRODUCTION/OBJECTIVES: To examine how people define Raynaud's phenomenon (RP) based on their lived experiences and explore if differences exist depending on primary or secondary RP diagnosis. METHOD: An international survey was sent to people with RP through health systems, foundations, and social media. Qualitative coding of responses to an open text question regarding one's own definition of RP was performed and themes were identified. The prevalence of themes among the sample and then comparisons between themes among people who self-reported primary versus secondary diagnosis of RP were performed. RESULTS: There were 1345 respondents from 45 countries (mean age 51.5 years, 93% female) who defined RP in their own words; 17% reported primary RP and 83% reported secondary RP (69% of secondary RP was scleroderma-related, n = 927). Over half defined their RP by describing the body parts affected, color changes, pain, and triggers or situations in which an episode occurs. Patients with primary RP more frequently defined RP in terms of its impact on function/quality of life and pain compared to those with secondary RP (34.5% versus 25.3%, respectively, p=0.004; 54.0% versus 46.8%, p=0.05). Patients with secondary RP more frequently included specific body parts, color change, the management of attacks, and other digital vascular complications in their definition of RP. CONCLUSIONS: We have identified differences in how people with primary and secondary RP define RP, in terms of how they feel and function. Our findings have implications for the domains of outcome measures for assessing RP within different patient populations. Key Points • Pain is more often mentioned in primary RP and color change in secondary RP. • Over 25% of patients included reduced the quality of life as part of their RP definition. • The concept of "attack" is used to define RP by only 2% of patients.

9.
Arthritis Res Ther ; 23(1): 10, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407866

RESUMO

BACKGROUND: Abnormalities in lymphocyte surface markers and functions have been described in systemic sclerosis (SSc), but conflicting results abound, and these studies often examined patients with heterogeneous disease duration, severity, clinical phenotype, and concurrent immunosuppressive agents. We studied a clinically homogeneous group of early diffuse cutaneous SSc patients not exposed to immunosuppressive drugs who were enrolled in a clinical trial and compared their immune parameters to healthy control subjects. METHODS: Lymphocyte subsets were enumerated by multi-parameter flow cytometry of peripheral blood mononuclear cells at baseline visit. Production of the cytokines IL-4 and IL-17 was measured by intracellular flow cytometry following T cell activation. RESULTS: SSc patients had increased percentages of CD4+ T cells but lower percentages of CD8+ T cells versus controls. The CD28-negative population was expanded in SSc, in the CD4 subset. Striking expansion of CD319+ T cells was noted among the CD4+ cells, in which they were barely detectable in healthy subjects. Frequencies of IL-4 producing cells did not differ between SSc and controls, but expansion of IL-17 producing cells was observed in SSc. A higher proportion of CD319+ cells produced cytokines, compared to other CD4+ cells. Numbers of activated T cells, regulatory T cells, and B cells were similar in SSc and control groups. Circulating follicular helper but not peripheral helper T cells were slightly expanded in SSc. CONCLUSION: In this carefully selected group of early diffuse cutaneous SSc patients, analysis of immune cell parameters has identified abnormalities that likely reflect disease pathogenesis and that are candidate biomarkers for sub-classification and targeted treatment. The CD4+CD319+ (SLAM-F7+) cells are cytotoxic and oligoclonal, were recently shown to be a dominant T cell population in perivascular lymphocytic infiltrates in SSc skin, actively secrete cytokines, and are emerging as a target for novel treatments of SSc.

10.
Ann Rheum Dis ; 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-33257497

RESUMO

OBJECTIVES: American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS) is a composite endpoint to assess the likelihood of improvement in diffuse systemic sclerosis. ACR-CRISS is a weighted score and includes five core set measures: modified Rodnan skin score, FVC% predicted, health assessment questionnaire-disability index, and patient and clinician global assessments. METHODS: We analysed core set measures from 354 participants who participated in three placebo-controlled trials. We generated 10 development datasets, randomly selected from 2/3 of the participants, stratified by study and treatment group. The remaining participants (1/3 of the participants) formed the validation sets. Risk differences (RDs) between active and placebo treatments were calculated by averaging over the replicate datasets; bootstrap 95% CIs for the RDs to estimate the magnitude of treatment effects. RESULTS: In the development sets (n=237), the proportion of participants in the active group had statistically higher improvement in >1 of 5 core set measures versus the placebo group. For example, the proportion who improved by ≥20% in ≥3 core set measures was 49.4% in the active versus338.9% in the placebo; RD: 10.5%, 95% CI4.9 % to 16.1%. In the validation sets (n=117), the proportion who improved by ≥20% in ≥3 core set measures was 50.3% in the active versus35.63% in the placebo (RD:114.8%, 95% CI 3.1% to225.7%). Similar trends were seen with larger percentage cut-offs. CONCLUSION: Revised CRISS, as assessed by the proportion of participants who improved by a certain percentage in ≥3 of 5 core set measures, is a potential new composite outcome measure.

11.
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.

12.
Curr Treatm Opt Rheumatol ; 6(4): 337-353, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33282632

RESUMO

Purpose of review: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is one of the most serious extra-articular RA manifestations. RA-ILD is associated with worse physical function, lower quality of life, and increased mortality. RA-ILD is comprised of heterogeneous subtypes characterized by inflammation and fibrosis. Diagnosis can be difficult since the presentation of RA-ILD is characterized by non-specific symptoms and imaging findings. Management of RA-ILD is also challenging due to difficulty in precisely measuring pulmonary disease activity and response to treatment in patients who may also have articular inflammation. We provide a current overview of RA-ILD focusing on prevalence, risk factors, and treatment. Recent findings: Research interest in RA-ILD has increased in recent years. Some studies suggest that RA-ILD prevalence may be increasing; this may be due to underlying biologic drivers or increases in imaging and recognition. Novel RA-ILD risk factors include the MUC5B promotor variant, articular disease activity, autoantibodies, and biomarkers of damaged pulmonary parenchyma. Treatment should focus on controlling RA disease activity, which emerging data suggest may reduce RA-ILD risk. Immunomodulatory and antifibrotic drugs may also treat RA-ILD. Summary: RA-ILD is an underrecognized and serious manifestation of RA, but important progress is being made in identifying risk factors and treatment.

13.
Cell Rep Med ; 1(8): 100140, 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33294861

RESUMO

Progressive lung fibrosis is a major cause of mortality in systemic sclerosis (SSc) patients, but the underlying mechanisms remain unclear. We demonstrate that immune complexes (ICs) activate human monocytes to promote lung fibroblast migration partly via osteopontin (OPN) secretion, which is amplified by autocrine monocyte colony stimulating factor (MCSF) and interleukin-6 (IL-6) activity. Bulk and single-cell RNA sequencing demonstrate that elevated OPN expression in SSc lung tissue is enriched in macrophages, partially overlapping with CCL18 expression. Serum OPN is elevated in SSc patients with interstitial lung disease (ILD) and prognosticates future lung function deterioration in SSc cohorts. Serum OPN levels decrease following tocilizumab (monoclonal anti-IL-6 receptor) treatment, confirming the connection between IL-6 and OPN in SSc patients. Collectively, these data suggest a plausible link between autoantibodies and lung fibrosis progression, where circulating OPN serves as a systemic proxy for IC-driven profibrotic macrophage activity, highlighting its potential as a promising biomarker in SSc ILD.

14.
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.

16.
Expert Opin Emerg Drugs ; : 1-12, 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33054463

RESUMO

INTRODUCTION: Systemic sclerosis (SSc) has the highest case-specific mortality of all connective tissue diseases. Its underlying disease mechanism affects several organs and remains incompletely understood. Ongoing work clarifying its etiopathogenesis is helping to develop targeted therapy. AREAS COVERED: Several clinical trials have evaluated the safety and efficacy of agents targeting different mechanisms of this disease. This review article reviews those mechanisms and surveys four key recent phase II or III clinical trials that are contributing to the landscape of SSc therapy. The reported trials primarily focus on patients with systemic sclerosis in the early phase of disease. EXPERT OPINION: Traditional therapies for SSc center on immunosuppressive and cytotoxic agents. A new cadre of therapies is borne from improved understandings of SSc pathobiology and target the inflammatory-fibrotic pathways. Scleroderma trials have entered the initial phase of personalized medicine, recognizing molecular subsets that will improve upon cohort enrichment and maximize the measurable benefit of future therapies.

17.
Clin Rheumatol ; 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33094395

RESUMO

The objective of this analysis is to examine whether the severity of systemic sclerosis (SSc)-hand involvement influences patient-reported outcome measure (PROM) completion rate in a US cohort of early disease. Participants included SSc patients with less than 5 years disease duration consented and enrolled in the Collaborative, National, Quality, and Efficacy Registry (CONQUER) between June 2018 and December 2019. Participants' socio-demographics, hand clinical features (severe modified Rodnan skin score, presence of small joint contractures, acro-osteolysis, calcinosis, and digital ulcers), and completion rates of seven PROMs including a Resource Use Questionnaire were analyzed. Cohort characteristics and baseline PROM completion were evaluated. Multivariable logistic regression assessed the relationship between hand limitations and PROM incompletion at several time points using generalized estimating equations. At the time of data lock, 339 CONQUER subjects had a total of 600 visits available for analysis. Calcinosis (odds ratio [OR] 6.35, confidence interval [CI] 2.41-16.73 and acro-osteolysis OR 3.88 (1.57-9.55) were significantly associated with incomplete PROM. The Resource Use Questionnaire was the PROM most commonly not completed. Increasing age was correlated with resource use questionnaire incompletion rate. Acro-osteolysis and calcinosis were associated with lower PROM completion rates in a US SSc cohort, independent of the length of the questionnaires or the modality of administration (electronic or paper). Resource Use Questionnaires are important for understanding the economic impact and burden of chronic disease; however, in this study, it had lower completion rates than PROMs devoted to clinical variables. Key points •Multiple strategies are needed to ensure optimal completion of PROM in longitudinal cohort studies. Even if patients request electronic surveys, we have found it is important to follow up incomplete surveys with paper forms provided at the time of a clinical visit. •The Resource Utilization Questionnaire was lengthy and prone to non-completion in the younger population. •Acro-osteolysis and calcinosis were associated with reduced PROM completion rates.

18.
Arthritis Rheumatol ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33001586

RESUMO

OBJECTIVES: Intravenous iloprost improves Raynaud's phenomenon (RP) and promotes healing of digital ulcers (DU) in scleroderma (SSc). Despite a short half-life, its clinical efficacy lasts weeks. Endothelial adherens junctions, which are formed by VE-cadherin clustering between endothelial cells (ECs), regulate endothelial properties including barrier function, endothelial to mesenchymal transition (Endo-MT), and angiogenesis. We hypothesized that junctional disruption contributes to vascular dysfunction in SSc, and that the protective effect of iloprost is mediated by strengthening of those junctions. METHODS: Dermal ECs from SSc patients and healthy controls were isolated. The effect of iloprost on ECs was examined using immunofluorescence, permeability assays, Matrigel tube formation, and quantitative PCR. RESULTS: Adherens junctions in SSc were disrupted compared to normal ECs, as indicated by reduced levels of VE-cadherin and increased permeability in SSc ECs (p<0.05). Iloprost increased VE-cadherin clustering at junctions and restored junctional levels of VE-cadherin in SSc ECs (37.3 ± 4.3 fluorescent unit, mean ± SD) compared to normals (29.7 ± 3.4, p<0.05) after 2 hours of iloprost incubation. In addition, iloprost reduced permeability of monolayers, increased tubulogenesis, and blocked Endo-MT in both normal and SSc ECs (n≥3, p<0.05). The effects in normal ECs were inhibited by a function-blocking antibody that prevents junctional clustering of VE-cadherin. CONCLUSIONS: Our data suggests that the long-lasting effects of iloprost reflect its ability to stabilize adherens junctions, resulting in increased tubulogenesis and barrier function, and reduced Endo-MT. These results provide a mechanistic basis for the use of iloprost in treating SSc patients with RP and DU.

19.
J Rheumatol ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004536

RESUMO

OBJECTIVE: To investigate the effects of abituzumab in systemic sclerosis-associated interstitial lung disease (SSc-ILD). METHODS: STRATUS was a Phase II, double-blind, parallel-group, multicenter trial (NCT02745145). Adults (≤75 years) with SSc-ILD on stable mycophenolate were randomized (2:2:1) to receive intravenous abituzumab 1500 mg, placebo, or abituzumab 500 mg every 4 weeks for 104 weeks. Primary endpoint: annual rate of change in absolute FVC. RESULTS: STRATUS was terminated prematurely due to slow enrolment (n=75 screened, n=24 randomized), precluding robust analysis of efficacy. Abituzumab was well-tolerated; no new safety signals were detected. CONCLUSION: Further investigation of abituzumab for treatment of SSc-ILD is required.

20.
Lancet Respir Med ; 8(10): 963-974, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32866440

RESUMO

BACKGROUND: A phase 2 trial of tocilizumab showed preliminary evidence of efficacy in systemic sclerosis. We assessed skin fibrosis and systemic sclerosis-associated interstitial lung disease (SSc-ILD) in a phase 3 trial to investigate the safety and efficacy of tocilizumab, an anti-interleukin-6 receptor antibody, in the treatment of systemic sclerosis. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial, participants were recruited from 75 sites in 20 countries across Europe, North America, Latin America, and Japan. Adults with diffuse cutaneous systemic sclerosis for 60 months or less and a modified Rodnan skin score (mRSS) of 10-35 at screening were randomly assigned (1:1) with a voice-web-response system to receive subcutaneous tocilizumab 162 mg or placebo weekly for 48 weeks, stratified by IL-6 levels; participants and investigators were masked to treatment group. The primary endpoint was the difference in change from baseline to week 48 in mRSS. Percentage of predicted forced vital capacity (FVC% predicted) at week 48, time to treatment failure, and patient-reported and physician-reported outcomes were secondary endpoints. This trial is registered with ClinicalTrials.gov (number NCT02453256) and is closed to accrual. FINDINGS: Between Nov 20, 2015, and Feb 14, 2017, 210 individuals were randomly assigned to receive tocilizumab (n=104) or placebo (n=106). In the intention-to-treat population, least squares mean [LSM] change from baseline to week 48 in mRSS was -6·14 for tocilizumab and -4·41 for placebo (adjusted difference -1·73 [95% CI -3·78 to 0·32]; p=0·10). The shift in distribution of change from baseline in FVC% predicted at week 48 favoured tocilizumab (van Elteren nominal p=0·002 vs placebo), with a difference in LSM of 4·2 (95% CI 2·0-6·4; nominal p=0·0002), as did time to treatment failure (hazard ratio 0·63 [95% CI 0·37-1·06]; nominal p=0·08). Change in LSM from baseline to week 48 in Health Assessment Questionnaire-Disability Index and in patient-global and physician-global visual analogue scale assessments did not differ between tocilizumab and placebo. In the safety set, infections were the most common adverse events (54 [52%] of 104 participants in the tocilizumab group, 53 [50%] of 106 in the placebo group). Serious adverse events were reported in 13 participants treated with tocilizumab and 18 with placebo, primarily infections (three events, eight events) and cardiac events (two events, seven events). INTERPRETATION: The primary skin fibrosis endpoint was not met. Findings for the secondary endpoint of FVC% predicted indicate that tocilizumab might preserve lung function in people with early SSc-ILD and elevated acute-phase reactants. Safety was consistent with the known profile of tocilizumab. FUNDING: F Hoffmann-La Roche Ltd.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Escleroderma Sistêmico/tratamento farmacológico , Adulto , Estudos de Coortes , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Capacidade Vital
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