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2.
Autoimmun Rev ; : 102458, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31927087

RESUMO

Capillaroscopy is a non-invasive and safe tool which allows the evaluation of the morphology of the microcirculation. Since its recent incorporation in the 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for systemic sclerosis together with its assessed role to monitor disease progression, capillaroscopy became a 'mainstream' investigation for rheumatologists. Given its increasing use by a variety of physicians internationally both in daily practice to differentiate primary from secondary Raynaud's phenomenon, as well as in research context to predict disease progression and monitor treatment effects, standardisation in capillaroscopic image acquisition and analysis seems paramount. To step forward to this need, experts in the field of capillaroscopy/microcirculation provide in this very consensus paper their view on image acquisition and analysis, different capillaroscopic techniques, normal and abnormal capillaroscopic characteristics and their meaning, scoring systems and reliability of image acquisition and interpretation.

3.
Clin Rheumatol ; 39(1): 93-102, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31667644

RESUMO

The Collaborative National Quality and Efficacy Registry (CONQUER) for Scleroderma is a multicenter US-based longitudinal study of patients with systemic sclerosis (SSc) within 5 years of first non-Raynaud's symptom. The data collection methodology incorporates successful models from other SSc registries. The cohort is designed to provide linked bio-specimen and clinical outcomes data on a longitudinal cohort of SSc patients for validation of hypothesis-driven research and to provide a platform for studying patient-reported outcomes in scleroderma. The CONQUER registry was developed using the guidelines of the International Society for Biological Repositories, and was an iterative process between physicians with an expertise in SSc, patient stakeholders, and information technology experts. Enrollment commenced in June 2018. During the first 6 months of the CONQUER Scleroderma study, 151 SSc patients with less than 5 years of disease duration (from first non-Raynaud's symptom) have been recruited. The mean age is 51 ± 14 years, 83% are female, and 60% of patients have diffuse disease. Survey completion rates are above 88% for all patient-reported outcome surveys. Bio-specimen collection rates are over 97%, and disease severity score completion rates are over 98%. Pulmonary function test data is available on 91% of patients, and echocardiography is available 80%. The CONQUER scleroderma study provides a unique and growing resource for studying scleroderma in a longitudinal, US-based population. KEY POINTS : • The Collaborative National Quality and Efficacy Registry (CONQUER) for Scleroderma is a multicenter US-based longitudinal study of patients with systemic sclerosis (SSc) within 5 years of first non-Raynaud's symptom. • The CONQUER scleroderma study provides a unique and growing resource for studying scleroderma in a longitudinal, US-based population. • CONQUER is innovative in its design in that it is focused on prospective collection of paired clinical and patient outcome data with bio-specimens.

4.
Arthritis Rheumatol ; 72(1): 125-136, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31342624

RESUMO

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

5.
Artigo em Inglês | MEDLINE | ID: mdl-31841265

RESUMO

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

6.
Ann Rheum Dis ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767698

RESUMO

OBJECTIVES: Determine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease. METHODS: Skin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated. RESULTS: SSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression. CONCLUSIONS: Skin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design.

7.
Curr Treatm Opt Rheumatol ; 5(1): 11-19, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31750073

RESUMO

Purpose of review: The goal of this manuscript is to discuss the new diagnostic and potential treatment options for gut disease in systemic sclerosis (SSc). The concepts of quantification of gut perfusion and motility is reviewed. The risks of empiric therapeutics and challenges of studying the microbiome in SSc is discussed. Recent findings: There are diagnostics that can provide information on gut perfusion and function that are of value in SSc. Easily implemented diagnostic tests are critical to avoid complications of empiric therapy. The role of the microbiome and drugs that target dysmotility are areas of active research. Summary: SSc-related gastrointestinal tract involvement can be heterogeneous in clinical presentation and disease course. Noninvasive gastrointestinal measurement techniques that quantify neural communications with microvasculature in SSc can potentially guide the proper addition and discontinuation of therapeutics. The role of the microbiome and the role of nitric oxide on gut function are important areas of research for understanding gut dysfunction in SSc.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31628482

RESUMO

OBJECTIVES: 3-hydroxy-3-methylglutaryl coenzyme-A (HMG Co-A) reductase inhibitors (statins) are standard treatment for hyperlipidaemia. In addition to lipid-lowering abilities, statins exhibit multiple anti-inflammatory effects. The objectives of this study were to determine whether treatment of patients with RA with lovastatin decreased CRP or reduced disease activity. METHODS: We conducted a randomized double-blind placebo-controlled 12 week trial of lovastatin vs placebo in 64 RA patients with mild clinical disease activity but an elevated CRP. The primary efficacy end point was the reduction in mean log CRP. Secondary end points included disease activity, RF and anti-CCP antibody titres. Mechanistic end points included levels of serum cytokines. Safety was assessed; hepatic and muscle toxicities were of particular interest. RESULTS: Baseline features were similar between groups. No significant difference in mean log CRP reduction between the two groups was observed, and disease activity did not change from baseline in either treatment group. Mechanistic analyses did not reveal significant changes in any biomarkers. A post hoc analysis of subjects not using biologic therapy demonstrated a significantly greater proportion achieving ⩾20% reduction in CRP from baseline in the lovastatin group compared with placebo (P-value = 0.007). No difference was observed in subjects receiving biologics. Lovastatin was well tolerated with no serious safety concerns. CONCLUSION: This study showed no anti-inflammatory or clinical effects on RA disease activity after 12 weeks of treatment with lovastatin. Lovastatin had a modest effect on CRP in subjects not using biologics, suggesting statins may be anti-inflammatory in selected patients. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT00302952.

9.
Clin Exp Rheumatol ; 37 Suppl 119(4): 97-101, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31573479

RESUMO

OBJECTIVES: The fingers, toes, and tips of the nose and ears have specialised structural and functional features for thermoregulation, and are the most common areas of Raynaud's phenomenon in systemic sclerosis. Digital thermal monitoring (DTM) of vascular reactivity assesses Doppler ultrasound hyperemic, low frequency, blood velocity of radial artery and fingertip vascular function. Flow mediated dilation (FMD) is an indirect measure of endothelial function, perfusion, and vasodilator ability. In this study, we investigated the cross-sectional correlation of FMD and DTM variables to inform an optimised noninvasive study of SSc endothelial function. A student's T-test was used to compare means of DTM across binary variables. METHODS: Consented SSc registry patients were included in this analysis. The subjects were prepared for FMD and DTM per standardised guidelines. The SSc clinical features were recorded. Spearman's Rank Correlation was used to assess the strength of a relationship FMD and DTM variables. RESULTS: Thirty-four SSc subjects had FMD and DTM performed on the same day. Relative (0.42, p=<0.02), absolute FMD (0.41, p<0.02), and shear rate (0.32, p<0.07) were weakly, but significantly correlated with the DTM. Reactive hyperemia (-0.44, p=0.000) was weakly inversely, but significantly related with DTM. Baseline diameter and flow were not significantly related to the DTM. CONCLUSIONS: This non-invasive study of SSc endothelial function suggests that macrocirculation (including relative and absolute FMD, shear rate, and peak hyperemia) and microcirculatory thermoregulation (characterised by DTM) are significantly correlated, thus warrants further prospective study.


Assuntos
Microcirculação/fisiologia , Fluxo Sanguíneo Regional/fisiologia , Escleroderma Sistêmico , Pele/irrigação sanguínea , Artéria Braquial , Estudos Transversais , Dilatação , Endotélio Vascular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Escleroderma Sistêmico/fisiopatologia , Vasodilatação
10.
Arthritis Res Ther ; 21(1): 202, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481106

RESUMO

BACKGROUND: To determine the effect of riociguat, an oral, selective soluble guanylate cyclase stimulator, on the net digital ulcer (DU) burden in systemic sclerosis (SSc). METHODS: Participants with SSc-related active or painful indeterminate DUs were recruited in a multicenter, double-blind, randomized, placebo-controlled, proof-of-concept trial. Eligible participants were required to have at least one visible, active ischemic DU or painful indeterminate DU at screening, located at or distal to the proximal interphalangeal joint and that developed or worsened within 8 weeks prior to screening. Participants were randomized 1:1 to placebo or riociguat in individualized doses (maximum of 2.5 mg three times daily) during an 8-week titration period, followed by an 8-week stable dosing period. This was followed by an optional 16-week open-label extension phase for participants with active DU/reoccurrence of DUs within 1 month of the end of the main treatment phase. The primary endpoint was the change from baseline to week 16 in net ulcer burden (NUB), analyzed using ANCOVA. Other endpoints included plasma biomarkers and proportion of participants with treatment-emergent adverse events (AEs). RESULTS: Seventeen participants (eight placebo, nine riociguat) were randomized at five centers. Six participants in each group transitioned to the open-label extension. Baseline characteristics were comparable between the treatment groups, except participants randomized to placebo were older and had longer disease duration (p < 0.05). At baseline, the mean (SD) NUB was 2.5 (2.0) in the placebo and 2.4 (1.4) in the riociguat. No significant treatment difference was observed in the change from baseline to 16 weeks in NUB (adjusted mean treatment difference - 0.24, 95% CI (- 1.46, 0.99), p = 0.70). Four participants experienced five serious AE (four in riociguat and one in placebo); none was considered related to study medication. Statistically significant elevation of cGMP was observed at 16 weeks in the riociguat group (p = 0.05); no other biomarkers showed significant changes. In the open-label extension, participants in the riociguat-riociguat arm had complete healing of their DUs. CONCLUSION: In participants with SSc-DU, treatment with riociguat did not reduce the number of DU net burden compared with placebo at 16 weeks. Open-label extension suggests that longer duration is needed to promote DU healing, which needs to be confirmed in a new trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02915835 . Registered on September 27, 2016.

11.
J Rheumatol ; 46(11): 1547, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31371652
12.
J Rheumatol ; 46(11): 1544-1545, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31308205
14.
J Scleroderma Relat Disord ; 4(1): 17-27, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30906878

RESUMO

The Scleroderma Clinical Trials Consortium (SCTC) represents many of the clinical researchers in the world who are interested in improving the efficiency of clinical trials in Systemic Sclerosis (SSc). The SCTC has established 11 working groups (WGs) to develop and validate better ways of measuring and recording multiple aspects of this heterogeneous disease. These include groups working on arthritis, disease damage, disease activity, cardiac disease, juvenile SSc, the gastrointestinal tract, vascular component, calcinosis, scleroderma renal crisis, interstitial lung disease, and skin measurement. Members of the SCTC may join any one or more of these groups. Some of the WGs have only recently started their work, some are nearing completion of their mandated tasks and others are in the midst of their projects. All these projects, which are described in this paper, will help to improve clinical trials and observational studies by improving or developing better, more sensitive ways of measuring various aspects of the disease. As Lord Kelvin stated, "To measure is to know. If you cannot measure it you cannot improve it." The SCTC is dedicated to improving the lives of patients with SSc and it is our hope that the contributions of the WGs will be one important step in this process.

15.
J Rheumatol ; 46(10): 1326-1334, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30824643

RESUMO

OBJECTIVE: Raynaud phenomenon (RP) in systemic sclerosis (SSc) could be influenced by clinical phenotype, environmental factors (e.g., season), and personal factors (e.g., coping strategies and ill-health perceptions). We studied the relative influence of a range of putative factors affecting patient-reported assessment of SSc-RP severity. METHODS: SSc patients were enrolled at UK and US sites. Participants completed the 2-week Raynaud Condition Score (RCS) diary alongside collection of patient demographics, clinical phenotype, the Coping Strategies Questionnaire, Pain Catastrophizing Scale, Scleroderma Health Assessment Questionnaire (SHAQ), and both patient/physician visual analog scale (VAS) assessments for RP, digital ulcer disease, and global disease. Environmental temperature data were obtained at each site. A second RCS diary was completed 6 months after enrollment. RESULTS: We enrolled 107 patients (baseline questionnaires returned by 94). There were significant associations between RCS diary variables and both catastrophizing and coping strategies. There were significant associations between RCS diary outcomes and both environmental temperature and season of enrollment. Age, disease duration, sex, disease subtype, smoking, and vasodilator use were not associated with RCS diary outcomes. The best-fitting multivariate model identified the patient RP VAS, SHAQ pain VAS, and SHAQ gastrointestinal VAS subscales as the strongest independent predictors of the RCS. CONCLUSION: Patient-reported assessment of SSc-RP severity is associated with a number of factors including pain, catastrophizing, and coping strategies. The effects of seasonal variation in environmental temperature on SSc-RP burden has implications for clinical trial design. Treatments targeting SSc-RP pain and the development of behavioral interventions enhancing coping strategies may reduce the burden of SSc-RP.

17.
Arthritis Rheumatol ; 71(6): 964-971, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30614663

RESUMO

OBJECTIVE: To generate a core set of items to develop classification criteria for scleroderma renal crisis (SRC) using consensus methodology. METHODS: An international, multidisciplinary panel of experts was invited to participate in a 3-round Delphi exercise developed using a survey based on items identified by a scoping review. In round 1, participants were asked to identify omissions and clarify ambiguities regarding the items in the survey. In round 2, participants were asked to rate the validity and feasibility of the items using Likert-type scales ranging from 1 to 9 (where 1 = very invalid/unfeasible, 5 = uncertain, and 9 = very valid/feasible). In round 3, participants reviewed the results and comments from round 2 and were asked to provide final ratings. Items rated as highly valid and feasible (median scores ≥7 for each) in round 3 were selected as the provisional core set of items. A consensus meeting using a nominal group technique was conducted to further reduce the core set of items. RESULTS: Ninety-nine experts from 16 countries participated in the Delphi exercise. Of the 31 items in the survey, consensus was achieved on 13, in the categories hypertension, renal insufficiency, proteinuria, and hemolysis. Eleven experts took part in the nominal group technique discussion, where consensus was achieved in 5 domains: blood pressure, acute kidney injury, microangiopathic hemolytic anemia, target organ dysfunction, and renal histopathology. CONCLUSION: A core set of items that characterize SRC was identified using consensus methodology. This core set will be used in future data-driven phases of this project to develop classification criteria for SRC.


Assuntos
Lesão Renal Aguda/classificação , Hipertensão Maligna/classificação , Rim/patologia , Escleroderma Sistêmico/complicações , Lesão Renal Aguda/etiologia , Anemia Hemolítica/classificação , Anemia Hemolítica/etiologia , Pressão Sanguínea , Técnica Delfos , Humanos , Hipertensão/classificação , Hipertensão/etiologia , Hipertensão Maligna/etiologia , Proteinúria/classificação , Proteinúria/etiologia , Índice de Gravidade de Doença
18.
J Rheumatol ; 46(1): 78-84, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30442827

RESUMO

OBJECTIVE: Validated gastrointestinal (GI) symptoms scales are used in clinical practice to assess patient-reported GI involvement. We sought to determine whether University of California, Los Angeles (UCLA) GI Tract Questionnaire (GIT) 2.0 Reflux scale, Patient-Reported Outcomes Measurement Information System (PROMIS) Reflux scale, and the Quality of Life in Reflux and Dyspepsia questionnaire (QOLRAD) are sensitive to identifying changes in GI symptoms following therapeutic intervention in participants with systemic sclerosis (SSc) and gastroesophageal reflux disease (GERD). METHODS: Participants with active GERD were recruited during clinical visits at 6 international SSc centers. Patient-reported outcome surveys and the GI self-reported questionnaire were completed at baseline and again at 4 weeks following a single intervention, and patients were classified as "improved" or "not improved." Effect size (ES) was calculated to assess the sensitivity to change. ES was interpreted as 0.50-0.79 as moderate effect and ≥ 0.80 as large effect. RESULTS: There were 116 participants with SSc and active GERD who enrolled. The average age was 53.8 years and mean disease duration was 12.0 years. The UCLA GIT 2.0 Reflux scale and PROMIS Reflux scale had a significant correlation at baseline (0.61, p < 0.0001), and both instruments correlated with the QOLRAD domains (-0.56 to -0.71). In participants who had the UCLA GIT 2.0, PROMIS Reflux scale, and QOLRAD administered over 2 timepoints (n = 57) and were classified as improved, the ES was large for the UCLA GIT 2.0 and PROMIS Reflux scale, and moderate to large across all QOLRAD domains. CONCLUSION: The UCLA GIT 2.0 Reflux scale, PROMIS Reflux scale, and QOLRAD are sensitive to change and can be included in future clinical trials.

19.
Arthritis Care Res (Hoboken) ; 71(8): 1119-1126, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30133174

RESUMO

OBJECTIVE: Assessment of Raynaud's phenomenon (RP) in systemic sclerosis (SSc) is reliant on self-report. The Raynaud's Condition Score (RCS) diary assumes discrete episodic RP attacks, although not all SSc patients identify with this paradigm. We investigated the clinical associations of SSc-RP symptom characteristics and the evolution of SSc-RP symptoms with disease progression. METHODS: A cross-sectional study at UK and US sites captured digital color changes of SSc-RP and patients' ability to identify with diagrammatic representations (and descriptive stems) of 4 distinct theoretical SSc-RP patterns (progressing severity A through D) reflecting progressively severe SSc-RP experiences. SSc-RP self-management and symptom evolution were explored. Patient demographics, the clinical phenotype, the Scleroderma Health Assessment Questionnaire (SHAQ), the 2-week RCS diary, and patient and physician global assessments were collected. RESULTS: We enrolled 107 patients with SSc (with questionnaires returned by 94). A higher number of self-reported digital color changes of SSc-RP were associated with increased SSc-RP symptom severity but not with the SSc clinical phenotype. Patients could identify with distinct patterns of SSc-RP. These patterns were associated with disease duration, global disease severity, and conceptually linked physician and patient assessments of peripheral vascular severity (e.g., SHAQ RP subscale and RCS diary parameters), but not with conceptually unrelated outcomes (e.g., SHAQ breathing subscale). SSc-RP characteristics and symptom severity evolve during the disease course. CONCLUSION: Patients identify with distinct patterns of SSc-RP that may relate to progression of the obliterative microangiopathy of SSc. Difficulty distinguishing discrete SSc-RP attacks from persistent digital ischemia in patients with advanced SSc could influence diary-based approaches to assessing SSc-RP, with implications for future clinical trials.

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