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3.
Eur Respir Rev ; 30(159)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33762426

RESUMO

Interstitial lung disease (ILD) affects approximately 50% of patients with systemic sclerosis (SSc) and is the leading cause of death in SSc. Our objective was to gain insight into the progression of SSc-associated ILD (SSc-ILD). Using data from longitudinal clinical trials and observational studies, we assessed definitions and patterns of progression, risk factors for progression, and implications for treatment. SSc-ILD progression was commonly defined as exceeding specific thresholds of lung function worsening and/or increasing radiographic involvement. One definition used in several studies is decline in forced vital capacity (FVC) of ≥10%, or ≥5-10% plus a decline in diffusing capacity of the lung for carbon monoxide ≥15%. Based on these criteria, 20-30% of patients in observational cohorts develop progressive ILD, starting early in the disease course and progressing at a highly variable rate.Risk factors such as age, FVC, extent of fibrosis and presence of anti-topoisomerase I antibodies can help predict progression of SSc-ILD, though composite risk scores may offer greater predictive power. Whilst the variability of the disease course in SSc-ILD makes risk stratification of patients challenging, the decision to initiate, change or stop treatment should be based on a combination of the current disease state and the speed of progression.

4.
Arthritis Rheumatol ; 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33605067

RESUMO

OBJECTIVE: To study the potential implication of semaphorins in the pathogenesis of rheumatoid arthritis (RA). PATIENT AND METHODS: microarray experiments were performed on Affymetrix GeneChip® Human Exon 1.0 ST Arrays in RA and control endothelial cell (ECs) derived from circulating progenitors. Expression of class 3 and 4 Semaphorins (SEMA) and their receptors was assessed by immunohistochemistry in the synovial tissue and by ELISA in the serum of RA patients and controls. RESULTS: micro-array analysis revealed differential expression of class 3/4 semaphorins and their receptors in RA ECs. SEMA4A, Plexin-D1 and neuropillin-1 mRNA levels were markedly increased in RA ECs by 1.75, 2.21 and 1.68 fold, respectively. TNFα stimulation led to a 2-fold increase of SEMA4A mRNA levels in RA ECs, and deficient SEMA4A expression modified RA EC angiogenic properties. Class 3/4 semaphorins as well as their receptors were overexpressed in RA synovial tissue. A respective 1.30 and 1.54-fold increase of SEMA4A and SEMA3E, as well as a 24% decrease of SEMA3A was detected in the serum of RA patients. SEMA4A, SEMA4D and SEMA3A serum levels correlated with inflammation and proangiogenic markers. In 2 independent cohorts of patients in low disease activity or remission, SEMA4A identified patients with residual disease activity. CONCLUSION: Gene expression profiling of ECs identified class 3/4 semaphorins as potential biomarkers and therapeutic candidates in RA, with confirmed overexpression in ECs, synovial vessels and serum, and correlation with validated markers of inflammation and angiogenesis. Thus, semaphorins might be novel and appealing EC-derived inflammatory and proangiogenic targets in RA.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33580257

RESUMO

OBJECTIVE: To evaluate clinical associations of anti-PM/Scl antibodies in patients with Systemic Sclerosis (SSc) in a multicentre international cohort, with particular focus on unresolved issues, including scleroderma renal crisis (SRC), malignancies, and functional outcome of interstitial lung disease (ILD). METHODS: (1) Analysis of SSc patients from the EUSTAR database: 144 anti-PM/Scl+ without SSc-specific autoantibodies were compared to 7,202 anti-PM/Scl-, and then to 155 anti-Pm/Scl+ with SSc-specific antibodies. (2) Case-control study: additional data were collected for 165 anti-PM/Scl+ SSc (85 from the EUSTAR registry), and compared to 257 anti-PM/Scl- SSc controls, matched for sex, cutaneous subset, disease duration, and age at SSc onset. RESULTS: Patients with isolated anti-PM/Scl positivity, as compared with anti-Pm/Scl-, had higher frequency of muscle involvement, ILD, calcinosis and cutaneous signs of dermatomyositis, but similar frequency of SRC and malignancies (either synchronous with SSc onset or not). The presence of muscle involvement was associated with a more severe disease phenotype. Although very frequent, ILD had a better functional outcome in cases than in controls.In patients with both anti-PM/Scl and SSc-specific antibodies, a higher frequency of typical SSc features than in those with isolated anti-PM/Scl was observed. CONCLUSION: The analysis of the largest series of anti-PM/Scl+ SSc patients so far reported helps to delineate a specific clinical subset with muscle involvement, cutaneous dermatomyositis, calcinosis, and ILD characterized by a good functional outcome. SRC and malignancies do not seem to be part of this syndrome.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33458774

RESUMO

OBJECTIVE: To study the profile of type-2 diabetes (T2D) in patients with RA or OA. METHODS: This observational, multicentre, cross-sectional study included, over a 24-month period, consecutive patients with adult-onset diabetes and RA or OA. We collected demographics, disease activity and severity indices, current treatments for RA and diabetes, history and complications of diabetes. A systematic blood test was performed, assessing inflammatory, immunological and metabolic parameters. The homoeostasis model assessment (HOMA)2-S was used to assess insulin resistance. RESULTS: We included 167 patients with T2D, 118 with RA and 49 with OA. RA and OA patients had severe T2D with suboptimal metabolic control and a biological profile of insulin resistance. Insulin resistance was significantly higher in RA than in OA patients after stratification on age, BMI and CS use [HOMA2-S: 63.5 (35.6) vs 98.4 (69.2), P < 0.001]. HOMA2-S was independently associated with DAS28 [odds ratio (OR): 4.46, 95% CI: 1.17, 17.08]. T2D metabolic control was not related to disease activity and functional impairment, but HbA1c levels were independently associated with bone erosions (OR: 4.43, 95% CI: 1.18, 16.61). Treatment with low-dose CSs was not associated with decreased insulin sensitivity or increased HbA1c levels. Treatment with TNF-α inhibitors was associated with increased insulin sensitivity compared with patients not receiving biologics [101.3 (58.71) vs 60.0 (32.5), P = 0.001]. CONCLUSION: RA patients display severe T2D with inflammation-associated insulin resistance. These findings may have therapeutic implications, with the potential targeting of insulin resistance through the treatment of joint and systemic inflammation.

7.
BMC Pulm Med ; 21(1): 13, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407317

RESUMO

BACKGROUND: There is only limited clinical data on the benefit of intense immunosuppression in patients with severe interstitial pneumonia associated with autoimmune features or new-onset connective tissue disease. CASE PRESENTATION: We here report a series of three consecutive patients suffering from severe interstitial lung disease necessitating endotracheal intubation and mechanical ventilation. The first two patients fulfilled many diagnostic criteria for new-onset antisynthetase syndrome, the third patient for systemic lupus erythematosus. We decided to implement aggressive immunosuppressive strategies in these critically-ill patients including therapeutic plasma exchange, immunoadsorption, cyclophosphamide and rituximab. All three patients improved from respiratory failure, were successfully weaned from the respirator, and eventually dismissed from hospital with ongoing immunosuppressive therapy. CONCLUSION: Patients suffering from severe connective tissue disease-associated interstitial lung disease and respiratory failure may benefit from an aggressive immunosuppressive regimen and extracorporeal blood purification with rapid reduction of circulating autoantibodies. The impressive clinical responses in this small case series warrant a controlled clinical trial.

8.
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
9.
Artigo em Inglês | MEDLINE | ID: mdl-33305638

RESUMO

OBJECTIVES: There are few comparative data for tumor necrosis factor inhibitors in patients with rheumatoid arthritis (RA). METHODS: Historical data for reference product/biosimilar intravenous infliximab, or adalimumab and etanercept, were pooled and compared with phase 3 study results for a subcutaneous (SC) formulation of the infliximab biosimilar CT-P13, in a systematic review and meta-analysis (PROSPERO: CRD42019149621). RESULTS: The authors identified 13 eligible controlled trials that randomized over 5400 participants to prespecified treatments of interest. Comparison with pooled historical data suggested a numerical advantage for CT-P13 SC over intravenous infliximab for almost every prespecified efficacy outcome evaluated, including Disease Activity Score in 28 joints (C-reactive protein/erythrocyte sedimentation rate), Clinical/Simplified Disease Activity Index scores, American College of Rheumatology responses, and multiple measures of disease remission and low disease activity; for the majority of outcomes, there was no overlap in 95% confidence intervals between groups. A numerical advantage for CT-P13 SC was also observed for safety outcomes (adverse events, infections and discontinuations). Similar, but less marked, trends were observed for comparison with historical efficacy and safety data for adalimumab/etanercept. CONCLUSION: CT-P13 SC offers an improved or similar benefit-to-harm ratio compared with infliximab (intravenous) and adalimumab/etanercept, for the treatment of moderate-to-severe RA.

10.
Eur J Rheumatol ; 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33226326

RESUMO

To date, scleroderma renal crisis (SRC) remains a life-threatening complication in patients affected by systemic sclerosis (SSc), with high morbidity and mortality. In the last few years, some studies have tried to more precisely identify predictors of SRC and clarify the role of previous drug exposure-in particular, angiotensin-converting enzyme (ACE) inhibitors and corticosteroids-in patients with SSc presenting other well-known risk factors for SRC. Different from the findings of previous reports, more recent findings suggest that the presence of chronic kidney disease, systemic arterial hypertension, and proteinuria might all be predictors of SRC. Moreover, because about 40 to 50% of SRC cases can present signs of microangiopathy, a recent study has proposed SSc thrombotic microangiopathy (SSc-TMA) as a clinically and pathophysiologically different entity from narrowly defined SRC. Even though such clear distinction may not always be applicable/feasible in clinical practice, it highlights that complement pathway dysregulation may play a key pathogenetic role in SRC presenting as TMA. Thus, plasma exchange may be considered in severe refractory cases. Nevertheless, ACE inhibitors and prompt achievement of blood pressure control (to rapidly improve ongoing renal ischemia) remain to date the cornerstone of SRC treatment. Here, we report the cases of three SSc patients with SRC followed at our rheumatology units. While describing these patients' risk factors, clinical presentation, and therapy, we aim to discuss the state of the art in SRC and highlight critical issues.

11.
Ann Rheum Dis ; 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004331

RESUMO

OBJECTIVES: Genomic Risk Scores (GRS) successfully demonstrated the ability of genetics to identify those individuals at high risk for complex traits including immune-mediated inflammatory diseases (IMIDs). We aimed to test the performance of GRS in the prediction of risk for systemic sclerosis (SSc) for the first time. METHODS: Allelic effects were obtained from the largest SSc Genome-Wide Association Study (GWAS) to date (9 095 SSc and 17 584 healthy controls with European ancestry). The best-fitting GRS was identified under the additive model in an independent cohort that comprised 400 patients with SSc and 571 controls. Additionally, GRS for clinical subtypes (limited cutaneous SSc and diffuse cutaneous SSc) and serological subtypes (anti-topoisomerase positive (ATA+) and anti-centromere positive (ACA+)) were generated. We combined the estimated GRS with demographic and immunological parameters in a multivariate generalised linear model. RESULTS: The best-fitting SSc GRS included 33 single nucleotide polymorphisms (SNPs) and discriminated between patients with SSc and controls (area under the receiver operating characteristic (ROC) curve (AUC)=0.673). Moreover, the GRS differentiated between SSc and other IMIDs, such as rheumatoid arthritis and Sjögren's syndrome. Finally, the combination of GRS with age and immune cell counts significantly increased the performance of the model (AUC=0.787). While the SSc GRS was not able to discriminate between ATA+ and ACA+ patients (AUC<0.5), the serological subtype GRS, which was based on the allelic effects observed for the comparison between ACA+ and ATA+ patients, reached an AUC=0.693. CONCLUSIONS: GRS was successfully implemented in SSc. The model discriminated between patients with SSc and controls or other IMIDs, confirming the potential of GRS to support early and differential diagnosis for SSc.

12.
Arthritis Res Ther ; 22(1): 257, 2020 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-33115544

RESUMO

BACKGROUND: Patients with diffuse cutaneous systemic sclerosis (dcSSc) have a poor prognosis. The importance of monitoring subjective measures of functioning and disability, such as the Health Assessment Questionnaire-Disability Index (HAQ-DI), is important as dcSSc is rated by patients as worse than diabetes or hemodialysis for quality of life impairment. This European Scleroderma Trials and Research (EUSTAR) database analysis was undertaken to examine the importance of impaired functionality in dcSSc prognosis. The primary objectives were to identify predictors of death and HAQ-DI score progression over 1 year. HAQ-DI score, major advanced organ involvement, and death rate were also used to develop a comprehensive model to predict lifetime dcSSc progression. METHODS: This was an observational, longitudinal study in patients with dcSSc registered in EUSTAR. Death and HAQ-DI scores were, respectively, analyzed by Cox regression and linear regression analyses in relation to baseline covariates. A microsimulation Markov model was developed to estimate/predict natural progression of dcSSc over a patient's lifetime. RESULTS: The analysis included dcSSc patients with (N = 690) and without (N = 4132) HAQ-DI score assessments from the EUSTAR database. Baseline HAQ-DI score, corticosteroid treatment, and major advanced organ involvement were predictive of death on multivariable analysis; a 1-point increase in baseline HAQ-DI score multiplied the risk of death by 2.7 (p <  0.001) and multiple advanced major organ involvement multiplied the risk of death by 2.8 (p <  0.05). Multivariable analysis showed that baseline modified Rodnan Skin Score (mRSS) and baseline HAQ-DI score were associated with HAQ-DI score progression at 1 year (p <  0.05), but there was no association between baseline organ involvement and HAQ-DI score progression at 1 year. HAQ-DI score, major advanced organ involvement, and death were successfully used to model long-term disease progression in dcSSc. CONCLUSIONS: HAQ-DI score and major advanced organ involvement were comparable predictors of mortality risk in dcSSc. Baseline mRSS and baseline HAQ-DI score were predictive of HAQ-DI score progression at 1 year, indicating a correlation between these endpoints in monitoring disease progression. It is hoped that this EUSTAR analysis may change physician perception about the importance of the HAQ-DI score in dcSSc.

13.
Expert Rev Clin Immunol ; : 1-10, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33076716

RESUMO

INTRODUCTION: The rarity of systemic sclerosis (SSc) and its widely heterogeneous presentation and disease course are the main limitations for clinical research. The European Scleroderma Trials and Research group (EUSTAR) was launchegd in 2004, aiming to unify research efforts in the field of SSc. The central EUSTAR database has grown exponentially over the years, promoting new research and clinical trials, shedding new light on SSc diagnosis, its clinical course and providing new ideas for state-of-the-art therapy.Areas covered: The authors summarized the key findings of the main EUSTAR studies by reviewing PubMed and Web-of-Science databases through July 2020. The authors focused on the very early diagnosis of SSc, the prediction of disease course and mortality, the evaluation of disease activity and quality of life, the general management and therapy. EXPERT OPINION: The findings elucidated in EUSTAR studies have substantially improved the diagnostic and therapeutic approach to SSc in the last 15 years. Further efforts are warranted to identify early prognostic markers of the disease and stratify patients who may benefit most from vasoactive, immunosuppressive, and/or antifibrotic therapy. This will be particularly important in leading the future of SSc toward precision medicine and to promote more targeted clinical trials.

14.
Ann Rheum Dis ; 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32988845

RESUMO

OBJECTIVES: To identify overall disease course, progression patterns and risk factors predictive for progressive interstitial lung disease (ILD) in patients with systemic sclerosis-associated ILD (SSc-ILD), using data from the European Scleroderma Trials And Research (EUSTAR) database over long-term follow-up. METHODS: Eligible patients with SSc-ILD were registered in the EUSTAR database and had measurements of forced vital capacity (FVC) at baseline and after 12±3 months. Long-term progressive ILD and progression patterns were assessed in patients with multiple FVC measurements. Potential predictors of ILD progression were analysed using multivariable mixed-effect models. RESULTS: 826 patients with SSc-ILD were included. Over 12±3 months, 219 (27%) showed progressive ILD: either moderate (FVC decline 5% to 10%) or significant (FVC decline >10%). A total of 535 (65%) patients had multiple FVC measurements available over mean 5-year follow-up. In each 12-month period, 23% to 27% of SSc-ILD patients showed progressive ILD, but only a minority of patients showed progression in consecutive periods. Most patients with progressive ILD (58%) had a pattern of slow lung function decline, with more periods of stability/improvement than decline, whereas only 8% showed rapid, continuously declining FVC; 178 (33%) experienced no episode of FVC decline. The strongest predictive factors for FVC decline over 5 years were male sex, higher modified Rodnan skin score and reflux/dysphagia symptoms. CONCLUSION: SSc-ILD shows a heterogeneous and variable disease course, and thus monitoring all patients closely is important. Novel treatment concepts, with treatment initiation before FVC decline occurs, should aim for prevention of progression to avoid irreversible organ damage.

15.
Joint Bone Spine ; 2020 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-32992030

RESUMO

OBJECTIVE: Systemic sclerosis (SSc) is a rare multisystem autoimmune disorder. It has a worldwide distribution but geographical and ethnic influences are poorly known. METHODS: The aim of the study was to compare demographic characteristics and frequency of internal organ system involvement of Black SSc patients to those of White SSc patients in France. Patient population included 425 SSc patients recruited at Cochin Hospital in Internal medicine and Rheumatology departments. Data were collected at the baseline visit, each Black patient was matched with 2 to 3 White controls from the same department. RESULTS: 105 Black patients and 320 White were included. Demographic comparison highlighted an older age for the White patients (48.66 ± 14.87 vs 39.56 ±10.79, P<0.0001). Phenotypic comparison showed more severe skin involvement for Black patients: they had more often diffuse skin involvement than White patients (69.2% vs. 44.7%, P<0.0001) with a higher baseline modified Rodnan skin score (15.8 vs. 11.3, P<0.001). Comparisons also showed more active ulcers (46.5% vs. 21.6%, P<0.001) and more common interstitial lung disease (73.7% vs. 43%, P<0.0001) for Black patients. Auto-antibody testing showed that White patients were more likely to harbor anti-centromere antibodies (ACA) (26.6% vs. 9%, P<0.001) whereas Black patients were more likely to have anti-U1RNP antibody (24.6% vs. 6.2%, P<0.0001). CONCLUSION: In this population recruited in a disease referral center, Black patients had more severe skin and lung involvements with lower prevalence of ACA as compared to White patients, supporting a more severe phenotype.

16.
Ann Rheum Dis ; 79(12): 1600-1607, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32963047

RESUMO

OBJECTIVES: Recent advances in systemic sclerosis (SSc) show that it involves a T-helper type-2-oriented immune response with interleukin (IL)-4 and IL-13. Romilkimab is an engineered, humanised, bispecific immunoglobulin-G4 antibody that binds and neutralises IL-4/IL-13 making it ideal for exploration in fibrosis. METHODS: Patients aged ≥18 years diagnosed with diffuse cutaneous SSc (dcSSc), and with or without immunosuppressive background therapy, were randomised (1:1) to subcutaneous romilkimab 200 mg or placebo one time per week for 24 weeks in this double-blind, proof-of-concept, phase II study. The primary endpoint was change in modified Rodnan skin score (mRSS) from baseline to week 24. RESULTS: Ninety-seven patients were randomised to romilkimab (n=48) or placebo (n=49) for 24 weeks. Least-squares mean (SE) change in mRSS was -4.76 (0.86) for romilkimab versus -2.45 (0.85) for placebo yielding a mean (SE) (90% CI) difference of -2.31 (1.21) (-4.32 to -0.31; p=0.0291, one-sided). Treatment-emergent AEs were balanced between placebo (n=41; 84%) and romilkimab (n=40; 80%). Most were mild-to-moderate and discontinuations were low (three overall). There were two deaths (one scleroderma renal crisis (romilkimab) and one cardiomyopathy (placebo)), neither were considered treatment related. Two patients in the placebo group had a cardiovascular treatment-emergent SAE (one cardiac failure, one cardiomyopathy), but there were no cardiac safety signals with romilkimab. CONCLUSION: This study demonstrated significant effects on skin changes with romilkimab in early dcSSc that require confirmation with a longer and more comprehensive phase III study to determine clinical relevance. TRIAL REGISTRATION NUMBER: NCT02921971.

17.
Clin Exp Rheumatol ; 38 Suppl 125(3): 161-168, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865169

RESUMO

OBJECTIVES: Both intravenous (IV) and oral (PO) cyclophosphamide (CYC) showed beneficial effects on skin and lung involvement in systemic sclerosis (SSc) in placebo-controlled randomised clinical trials and observational studies. Our goal was to compare the relative efficacy and safety of PO- versus IV-CYC for treating interstitial lung disease and/or skin involvement in SSc. METHODS: Patients were derived from the EUSTAR centres and the Scleroderma Lung Studies I and II. A minimum of 6 months of CYC treatment and 12 months follow-up were required. Serious (SAEs) and non-serious adverse events and efficacy data (change in FVC%, DLCO%, mRSS) were analysed at the end of CYC treatment (EoT) and at follow-up (FU). Analysis included descriptive statistics and linear regressions. RESULTS: Differences in ethnicity, previous DMARD exposure, previous and concomitant steroid exposure/dosage were observed in the PO (n=149) and IV (n=153) CYC groups. Adjusted and unadjusted changes in FVC%, DLCO% and mRSS were similar irrespective of mode of administration. PO patients had more leukopenia (p<0.001), haemorrhagic cystitis (p=0.011) and alopecia (p<0.001) at the EoT visit, while the IV group had more SAEs (p=0.025) and need for oxygen supplementation at FU (p=0.049). CONCLUSIONS: In a comparison of PO- to IV-CYC for SSc, we found no differences in lung function or cutaneous sclerosis after one year. Some differences in side effects were seen. The results need to be considered as preliminary; however, because we needed to use a combination of RCT and registry data, with some differences in demographics and concomitant medications, well-controlled studies are warranted.


Assuntos
Imunossupressores , Escleroderma Sistêmico , Ciclofosfamida , Fibrose , Humanos , Pulmão , Resultado do Tratamento
18.
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
19.
Curr Opin Rheumatol ; 32(6): 505-514, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32826477

RESUMO

PURPOSE OF REVIEW: To review susceptibility genes and how they could integrate in systemic sclerosis (SSc) pathophysiology providing insight and perspectives for innovative therapies. RECENT FINDINGS: SSc is a rare disease characterized by vasculopathy, dysregulated immunity and fibrosis. Genome-Wide association studies and ImmunoChip studies performed in recent years revealed associated genetic variants mainly localized in noncoding regions and mostly affecting the immune system of SSc patients. Gene variants were described in innate immunity (IRF5, IRF7 and TLR2), T and B cells activation (CD247, TNFAIP3, STAT4 and BLK) and NF-κB pathway (TNFAIP3 and TNIP1) confirming previous biological data. In addition to impacting immune response, CSK, DDX6, DNASE1L3 and GSDMA/B could also act in the vascular and fibrotic components of SSc. SUMMARY: Although genetic studies highlighted the dysregulated immune response in SSc, future research must focus on a deeper characterization of these variants with determination of their functional effects. Moreover, the role of these genes or others on specific vasculopathy and fibrosis would provide insight. Establishment of polygenic score or integrated genome approaches could identify new targets specific of SSc clinical features. This will allow physicians to propose new therapies to SSc patients.

20.
Eur Respir J ; 2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32646919

RESUMO

QUESTION ADDRESSED BY THE STUDY: Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Fibrotic interstitial lung disease (ILD) is a common complication of RA. Whether MTX exposure increases the risk of ILD in patients with RA is disputed. We aimed to evaluate the association of prior MTX use with development of RA-ILD. METHODS: Through a case-control study design with discovery and international replication samples, we examined the association of MTX exposure with ILD in 410 patients with chronic fibrotic ILD associated with RA (RA-ILD) and 673 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques. RESULTS: Analysis of the discovery sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted odds ratio [OR], 0.46; 95% confidence interval [CI], 0.24-0.90; p=0.022), which was confirmed in the replication samples (pooled adjusted OR, 0.39; 95% CI, 0.19-0.79; p=0.009). The combined estimate using both the derivation and validation samples revealed an adjusted OR of 0.43 (95% CI, 0.26-0.69; p=0.0006). MTX ever users were less frequent among patients with RA-ILD compared to those without ILD, irrespective of chest high resolution computed tomography pattern. In patients with RA-ILD, ILD detection was significantly delayed in MTX ever users compared to never users (11.4±10.4 years and 4.0±7.4 years, respectively; p<0.001). ANSWER TO THE QUESTION: Our results suggest that MTX use is not associated with an increased risk of RA-ILD in patients with RA, and that ILD was detected later in MTX treated patients.

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