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1.
Aliment Pharmacol Ther ; 53(7): 830-843, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33565643

RESUMO

BACKGROUND: Cirrhosis develops in <10% of individuals homozygous for the C282Y variant in the homeostatic iron regulator (HFE) gene. Carriage of PCSK7:rs236918 is associated with an increased risk of cirrhosis in this population. AIM: To determine if genetic variants significantly associated with the risk of alcohol- and NAFLD-related cirrhosis also modulate the cirrhosis risk in C282Y homozygotes. METHODS: Variants in PCSK7, PNPLA3, TM6SF2, MBOAT7 and HSD17B13 were genotyped in 1319 C282Y homozygotes, from six European countries, of whom 171 (13.0%) had cirrhosis. Genotypic and allelic associations with the risk for developing cirrhosis were assessed, adjusting for age and sex. Fixed effects meta-analyses of the adjusted summary data for each country were performed. Post hoc association testing was undertaken in the 131 (76.6%) cases and 299 (26.0%) controls with available liver histology. RESULTS: Significant associations were observed between PCSK7:rs236918 (OR = 1.52 [95% CI 1.06-2.19]; P = 0.022; I2  = 0%); PNPLA3:rs738409 (OR = 1.60 [95% CI 1.22-2.11]; P = 7.37 × 10-4 ; I2  = 45.5%) and TM6SF2:rs58542926 (OR = 1.94 [95% CI 1.28-2.95]; P = 1.86 × 10-3 ; I2  = 0%) and the cirrhosis risk in C282Y homozygotes. These findings remained significant in the subpopulation with available liver histology. The population-attributable fractions were 5.6% for PCSK7:rs236918, 13.8% for PNPLA3:rs738409, 6.5% for TM6SF2:rs58542926 and 24.0% for carriage of all three variants combined. CONCLUSIONS: The risk of cirrhosis associated with carriage of PCSK7:rs236918 was confirmed in this much larger population of C282Y homozygotes. In addition, PNPLA3:rs738409 and TM6SF2:rs58542926 were established as significant additional risk factors. More detailed genetic testing of C282Y homozygotes would allow risk stratification and help guide future management.


Assuntos
Hemocromatose , Hepatopatia Gordurosa não Alcoólica , Europa (Continente) , Genótipo , Humanos , Lipase/genética , Cirrose Hepática/etiologia , Cirrose Hepática/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Subtilisinas
3.
Artigo em Inglês | MEDLINE | ID: mdl-33468347

RESUMO

OBJECTIVE: This study aimed to develop (1) a new ultrasound definition for aggregates and (2) a semi-quantitative ultrasound scoring system (0-3) for tophus, double contour and aggregates. Furthermore, the intra- and inter-reader reliabilities of both the re-defined aggregates and the semi-quantitative scoring system were assessed using static image exercises. METHODS: Thirty-seven rheumatologists were invited. A Delphi process was used for re-defining aggregates and for selecting a semi-quantitative scoring system with >75% agreement obligate for reaching consensus. Subsequently, a web-based exercise on static ultrasound images was conducted in order to assess the reliability of both the re-defined aggregates and the semi-quantitative scoring system. RESULTS: Twenty rheumatologists contributed to all rounds of the Delphi and image exercises. A consensual re-definition of aggregates was obtained after three Delphi rounds but needed an overarching principle for scoring aggregates in patients. A consensus-based semi-quantitative ultrasound scoring system for gout lesions was developed after two Delphi rounds. The re-definition of aggregates showed good intra- and inter-reader reliability (κ-values 0.71 and 0.61). The reliabilities of the scoring system were good for all lesions with slightly higher intra-reader (κ-values 0.74-0.80) than inter-reader reliabilities (κ-values 0.61-0.67). CONCLUSION: A re-definition of aggregates was obtained with a good reliability when assessing static images. The first consensus-based semi-quantitative ultrasound scoring system for gout-specific lesions was developed with good inter- and intra-reader reliability for all lesions when tested in static images. The next step is to assess the reliabilities when scoring lesions in patients.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33272608

RESUMO

OBJECTIVES: Predictive data for the development of aortic dilatation (AD) in giant-cell arteritis (GCA) are controversial. The aim was to investigate by computed tomography (CT) the prevalence of AD in a consecutive cohort of GCA patients and controls, and to identify possible predictors for AD. METHODS: GCA patients and controls were identified by electronic search and underwent aortic contrast enhanced CT defining AD by aortic diameter adjusted to age, gender and body surface area. Pulse-wave velocity, intima-media thickness (IMT) and laboratory studies including lymphocyte subsets were conducted identifying potential factors associated with AD. Clinical and laboratory parameters at disease onset, occurrence of aortic rupture/dissection before and up to five years after study visit were retrieved by chart review. RESULTS: 144 GCA patients and 115 controls were included. GCA patients developed more frequently AD of the ascending and thoracic descending aorta compared to controls (OR 2.60, p = 0.016; OR 3.65, p = 0.005, respectively). Factors associated with AD development of thoracic descending aorta, but not of the ascending aorta, were higher percentages of circulating CD3+CD4+ cells, higher CD4/CD8 ratio, presence of polymyalgia rheumatica and increased carotid IMT at disease onset (OR range 1.10-3.11, all with p < 0.05). During follow-up, no GCA patient required surgical aortic repair or suffered aortic rupture/dissection. CONCLUSIONS: Thoracic but not abdominal ADs occur more commonly in GCA patients, however, the subsequent risk for aortic repair, rupture or dissection is low. Changes of T-cell subsets, presence of polymyalgia rheumatica and increased carotid IMT at disease onset are associated with AD development.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33200216

RESUMO

PMR is an inflammatory rheumatic disease of elderly people characterized by pain and stiffness in the neck, shoulder and pelvic girdles. No specific diagnostic confirmatory tests exist and clinical symptoms, as well as increased acute phase reactants, are unspecific. The diagnostic value of imaging including ultrasound, MRI and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) with/without CT for PMR is increasingly studied. These techniques, particularly FDG-PET/CT, may help to detect underlying GCA in PMR patients with an incomplete response to glucocorticoids and/or recurrent relapses. Recent imaging studies provide novel insights into the anatomical basis of inflammation in PMR, particularly at hip and spine, which may help to distinguish this disease from other mimicking conditions. In this review, we discuss novel insights into the pathoanatomy of PMR, compare the diagnostic values of different imaging techniques and summarize current data on the role of imaging for monitoring and outcome prediction.

7.
Front Med (Lausanne) ; 7: 562142, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33154972

RESUMO

In December 2019, a cluster of severe pneumonia was observed in China, with the subsequent discovery of a new beta-coronavirus (SARS-CoV-2) as the causative agent. The elicited disease COVID-19 is characterized by fever, dry cough, myalgia, or fatigue and has a favorable outcome in the majority of cases. However, in some patients COVID-19 leads to severe pneumonia and sepsis with subsequent respiratory failure and gastrointestinal, hematological, neurological, and cardiovascular complications. A higher risk of infection is intrinsic to active rheumatic and musculoskeletal diseases (RMD) and the use of biological disease modifying anti-rheumatic drugs (DMARDs). With an increasing number of reports on COVID-19 in RMD patients, we are beginning to appraise their risks. In this review, we summarize the published cases of COVID-19 infections in RMD patients, including patients with inflammatory arthritis and connective tissue diseases as well as anti-phospholipid syndrome and Kawasaki syndrome. Overall, patients with inflammatory arthritis do not seem to be at a higher risk for infection or a severe course of COVID-19. Risk for critical COVID-19 in patients with systemic inflammatory diseases such as SLE or vasculitis might be increased, but this needs further confirmation. Furthermore, we summarize the data on DMARDs used to fight SARS-CoV-2 infection and hyperinflammation.

8.
Ann Rheum Dis ; 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33158877

RESUMO

OBJECTIVES: To investigate how the first wave of COVID-19 pandemic influenced decisions of rheumatologists and health professionals in rheumatology regarding the management of patients with inflammatory rheumatic and musculoskeletal diseases (RMDs). METHODS: An English-language questionnaire was developed by a EULAR working group and distributed via national rheumatology societies of EULAR countries, EMEUNET and individual working group members. Responses were collected using an online survey tool. Descriptive statistics were calculated. RESULTS: We analysed 1286 responses from 35/45 EULAR countries. Due to containment measures, 82% of respondents indicated cancellation/postponement of face-to-face visits of new patients (84% of them offering remote consultation) and 91% of follow-up visits (96% with remote consultation). The majority of respondents (58%) perceived that the interval between symptom onset and first rheumatological consultations was longer during containment restrictions than before. Treatment decisions were frequently postponed (34%), and the majority (74%) of respondents stated that it was less likely to start a biological disease modifying anti-rheumatic drug (DMARD)/targeted synthetic DMARD during the pandemic, mainly because of patients' fear, limited availability of screening procedures and decreased availability of rheumatological services. Use of (hydroxy)chloroquine (HCQ) and tocilizumab (TCZ) for the COVID-19 indication was reported by 47% and 42% of respondents, respectively, leading to a shortage of these drugs for RMDs indications according to 49% and 14% of respondents, respectively. CONCLUSION: Measures related to containment of COVID-19 pandemic led to a perceived delay between symptom onset and a first rheumatological visit, postponement of treatment decisions, and shortage of HCQ and TCZ, thereby negatively impacting early treatment and treat-to-target strategies.

10.
Front Med (Lausanne) ; 7: 551, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33015101

RESUMO

Background: In polymyalgia rheumatica (PMR), data on bone turnover markers (BTM), on Wnt inhibitors (Dkk-1, sclerostin) and their changes induced by glucocorticoids (GC) are lacking. The aims of our study were to compare the baseline levels of Wnt inhibitors and BTM in PMR patients with healthy controls (HC) and to study their changes over the first 4 weeks of GC treatment. Materials and Methods: We enrolled 17 treatment-naïve patients affected by PMR and 17 age and sex-matched healthy controls (HC) from retired hospital personnel. PMR patients were administered methylprednisolone 16 mg daily for 4 weeks. Blood samples were taken at baseline and at week 4 for the PMR group, a single sample was taken for HC. N-propeptide of type I collagen (PINP), C-terminal telopeptide of type I collagen (CTX-I), sclerostin, Dkk-1, and C-reactive protein (CRP) were dosed. Results: At baseline, Dkk-1 was significantly higher in the PMR group as compared to HC (p = 0.002) while PINP, CTX-I and sclerostin levels were comparable between PMR patients and HC, After 4 weeks of GC treatment we found in the PMR group a decrease of PINP (mean ± SD percentage decrement as compared to baseline -40 ± 18.6%, p < 0.001), CTX-I (-23.5 ± 41.3%, p = 0.032), Dkk-1 (-22.4 ± 39.6, p = 0.033), and sclerostin (-32.49 ± 20.47, p < 0.001) as compared to baseline levels. Conclusions: In treatment-naïve PMR, systemic inflammation is associated with a dysregulation of the Wnt system (increased Dkk-1). Within the 1st month, treatment with GC showed noteworthy effects on bone resorption, formation, and on Wnt pathway modulators.

12.
Nat Rev Rheumatol ; 16(11): 662, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32913336

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

13.
15.
Nat Rev Rheumatol ; 16(9): 481-495, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32759996

RESUMO

Giant cell arteritis (GCA) is the most common type of primary vasculitis in Western countries. Polymyalgia rheumatica (PMR) is the second most common inflammatory rheumatic disease of the elderly after rheumatoid arthritis. Glucocorticoids are the cornerstone of treatment for GCA and PMR, which are interrelated diseases. Glucocorticoids are effective, but adverse effects occur in a high proportion of patients. Careful use of glucocorticoids and the application of preventive strategies can minimize these adverse effects. Possible long-term complications of GCA include aneurysm and stenosis of vessels, even in patients with apparently clinically inactive disease; acute blindness is rare during glucocorticoid treatment. In PMR, whether subclinical chronic inflammation can lead to long-term damage is less clear. Management of both GCA and PMR is hampered by the lack of universally accepted definitions of remission and other disease states, such as low disease activity or vessel damage without active disease. In this Review, we outline current evidence on the monitoring and long-term management of patients with GCA and PMR, including the tapering of treatment.

16.
Front Med (Lausanne) ; 7: 141, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32457913

RESUMO

Background: Differential diagnosis in early arthritis is challenging, especially early after symptom onset. Several studies applied musculoskeletal ultrasound in this setting, however, its role in helping diagnosis has yet to be clearly defined. The purpose of this work is to systematically assess the diagnostic applications of ultrasonography in early arthritis in order to summarize the available evidence and highlight possible gaps in knowledge. Methods: In December 2017, existing systematic literature reviews (SLR) on rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PsA), polymyalgia rheumatica (PMR), calcium pyrophosphate deposition disease (CPPD), and gout were retrieved. Studies on ultrasound to diagnose the target conditions and detecting elementary lesions (such as synovitis, tenosynovitis, enthesitis, bone erosions, osteophytes) were extracted from the SLRs. The searches of the previous reviews were updated and data from new studies fulfilling the inclusion criteria extracted. Groups of reviewers worked separately for each disease, when possible diagnostic accuracy (sensitivities, specificities) was calculated from primary studies. When available, the reliability of ultrasound to detect elementary lesions was extracted. Results: For all the examined disease, recent SLRs were available. The new searches identified 27 eligible articles, with 87 articles included from the previous SLRs. The diagnostic performance of ultrasound in identifying diseases was addressed by 75 studies; in most of them, a single elementary lesion was used to define diagnosis, except for PMR. Only studies on RA included consecutive patients with new onset of arthritis, while studies on gout and CPPD often focused on subjects with mono-arthritis. Most of the remaining studies enrolled patients with a defined diagnosis. Synovitis was the most frequently detected lesion; clinical diagnosis was the most common reference standard. The diagnostic performance of ultrasound across different conditions was extremely variable. Ultrasound to identify elementary lesions was assessed in 38 studies in OA, gout and CPPD. Its performance in OA was very variable, with better results in CPPD and gout. The reliability of ultrasound was moderate to good for most lesions. Conclusions: Although a consistent amount of literature investigated the diagnostic application of ultrasound, in only a minority of cases its additional value over clinical diagnosis was tested. This SLR underlines the need for studies with a pragmatic design to identify the placement of ultrasound in the diagnostic pathway of new-onset arthritis.

17.
Artigo em Inglês | MEDLINE | ID: mdl-32227243

RESUMO

OBJECTIVE: To investigate peripheral lymphopenia, a frequent finding in primary Sjögren's syndrome (pSS) associated with higher disease activity and increased mortality. METHODS: Prospective, cross-sectional study of consecutive patients with pSS (n = 66) and healthy controls (n = 181). Lymphocyte subsets were analysed by flow cytometry, naïve (CD45RA+) and memory (CD45RO+) CD4+ T cells were purified by MACS technology. In vitro proliferation and senescence-associated ß-galactosidase (SABG) were assessed by flow cytometry. Telomere length and TCR excision circles (TREC) were measured by real-time PCR. Telomerase activity was analysed according to the telomeric repeat amplification protocols (TRAP). RESULTS: In pSS, lymphopenia mainly affected naïve CD4+ T cells. We noted a lower frequency of proliferating naïve CD4+ T cells ex vivo and decreased homeostatic proliferation in response to IL-7 stimulation in vitro. Furthermore, naïve CD4+ T cells exhibited signs of immune cell aging including shortened telomeres, a reduction in IL-7R expression and accumulation of SABG. The senescent phenotype could be explained by telomerase insufficiency and drastically reduced levels of T-cell receptor excision circles (TRECs), indicating a history of extensive post-thymic cell division. TRECs correlated with the number of naïve CD4+ T cells linking the extend of earlier proliferation to the inability to sustain normal cell numbers. CONCLUSION: In pSS, evidence for increased proliferation of naïve CD4+ T cells earlier in life is associated with a senescent phenotype unable to sustain homeostasis. The lack of naïve CD4+ T cells forms the basis of lymphopenia frequently observed in pSS.

18.
Rheumatology (Oxford) ; 59(10): 2893-2897, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32091097

RESUMO

OBJECTIVES: The aim of this prospective study was to examine whether ultrasound or clinical abnormalities at enthesal sites predict radiographic progression at entheses in psoriatic arthritis (PsA). METHODS: Consecutive PsA patients were included and subjected to clinical and ultrasound assessments at 14 entheses at baseline, 6 and 12 months. Radiographs were performed at 0 and 12 months. By US, we investigated structural (erosions, osteophytes) and inflammatory changes [grey scale (0-32) and power Doppler (0-14, range global ultrasound score 0-140)], and radiographs were evaluated for enthesophytes and erosions (score range 0-56). Multivariate regression models were conducted to identify the possible association of clinical and ultrasound findings with radiographic progression. RESULTS: We examined 83 patients at baseline, of whom 43 (51.8%) had complete clinical, ultrasound and X-ray data. Twenty-four of 43 patients (55.8%) developed radiographic progression of entheses. These patients were younger (49.6 vs 59.3, P =0.005), had shorter disease duration (9.7 vs 17.9 years, P=0.015) and lower clinical disease activity at 6-months [disease activity in psoriatic arthritis (DAPSA) 6.7 vs 17.0, P=0.018] as compared with patients without progression. Non-progressors had higher ultrasound enthesophyte scores at baseline than progressors (20 vs 15, P<0.05). The multivariate regression analysis revealed that 48.6% of the variance of the X-ray score at 12-months follow-up (RegcoeffB = 0.827, P=0.000) could be explained by the baseline US enthesophyte score. CONCLUSION: Our data indicate that radiographic progression at entheses is linked with age, disease duration and ultrasound verified enthesophytes at baseline. No other ultrasound parameter predicted radiographic progression at entheses.

19.
J Rheumatol ; 47(9): 1379-1384, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32007937

RESUMO

OBJECTIVE: To survey participants with polymyalgia rheumatica (PMR) to evaluate the face validity, acceptability, and domain match of proposed candidate outcome measures. METHODS: A structured, online, anonymous survey was disseminated by patient support groups through their networks and online forums. The candidate outcome measures comprised (1) visual analog scale (VAS) and numerical rating score (NRS) to assess pain; (2) VAS, NRS, and duration to assess stiffness; (3) the modified Health Assessment Questionnaire and Health Assessment Questionnaire Disability Index to assess physical function; and (4) C-reactive protein and erythrocyte sedimentation rate to assess inflammation. Free-text answers were analyzed using descriptive thematic analysis to determine respondents' views of the candidate instruments. RESULTS: Seventy-eight people with PMR from 6 countries (UK, France, USA, Canada, Australia, and New Zealand) participated in the survey. Most respondents agreed candidate instruments were acceptable or "good to go." Free-text analysis identified 5 themes that participants considered inadequately covered by the proposed instruments. These related to (1) the variability, context, and location of pain; (2) the variability of stiffness; (3) fatigue; (4) disability; and (5) the correlation of inflammatory marker levels and severity of symptoms, sometimes reflecting disease activity and other times not. CONCLUSION: Participants reported additional aspects of their experience that are not covered by the proposed instruments, particularly for the experience of stiffness and effect of fatigue. New patient-reported outcome measures are required to increase the relevance of results from clinical trials to patients with PMR.

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