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1.
J Bone Miner Res ; 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33534144

RESUMO

After trauma, the formed fracture hematoma within the fracture gap contains all the important components (immune/stem cells, mediators) to initiate bone regeneration immediately. Thus, it is of great importance but also the most susceptible to negative influences. To study the interaction between bone and immune cells within the fracture gap, up-to-date in vitro systems should be capable of recapitulating cellular and humoral interactions and the physicochemical microenvironment (eg, hypoxia). Here, we first developed and characterized scaffold-free bone-like constructs (SFBCs), which were produced from bone marrow-derived mesenchymal stromal cells (MSCs) using a macroscale mesenchymal condensation approach. SFBCs revealed permeating mineralization characterized by increased bone volume (µCT, histology) and expression of osteogenic markers (RUNX2, SPP1, RANKL). Fracture hematoma (FH) models, consisting of human peripheral blood (immune cells) mixed with MSCs, were co-cultivated with SFBCs under hypoxic conditions. As a result, FH models revealed an increased expression of osteogenic (RUNX2, SPP1), angiogenic (MMP2, VEGF), HIF-related (LDHA, PGK1), and inflammatory (IL6, IL8) markers after 12 and 48 hours co-cultivation. Osteogenic and angiogenic gene expression of the FH indicate the osteoinductive potential and, thus, the biological functionality of the SFBCs. IL-6, IL-8, GM-CSF, and MIP-1ß were detectable within the supernatant after 24 and 48 hours of co-cultivation. To confirm the responsiveness of our model to modifying substances (eg, therapeutics), we used deferoxamine (DFO), which is well known to induce a cellular hypoxic adaptation response. Indeed, DFO particularly increased hypoxia-adaptive, osteogenic, and angiogenic processes within the FH models but had little effect on the SFBCs, indicating different response dynamics within the co-cultivation system. Therefore, based on our data, we have successfully modeled processes within the initial fracture healing phase in vitro and concluded that the cross-talk between bone and immune cells in the initial fracture healing phase is of particular importance for preclinical studies. © 2021 American Society for Bone and Mineral Research (ASBMR).

5.
Int J Mol Sci ; 22(1)2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33374446

RESUMO

Adequate tissue engineered models are required to further understand the (patho)physiological mechanism involved in the destructive processes of cartilage and subchondral bone during rheumatoid arthritis (RA). Therefore, we developed a human in vitro 3D osteochondral tissue model (OTM), mimicking cytokine-induced cellular and matrix-related changes leading to cartilage degradation and bone destruction in order to ultimately provide a preclinical drug screening tool. To this end, the OTM was engineered by co-cultivation of mesenchymal stromal cell (MSC)-derived bone and cartilage components in a 3D environment. It was comprehensively characterized on cell, protein, and mRNA level. Stimulating the OTM with pro-inflammatory cytokines, relevant in RA (tumor necrosis factor α, interleukin-6, macrophage migration inhibitory factor), caused cell- and matrix-related changes, resulting in a significantly induced gene expression of lactate dehydrogenase A, interleukin-8 and tumor necrosis factor α in both, cartilage and bone, while the matrix metalloproteases 1 and 3 were only induced in cartilage. Finally, application of target-specific drugs prevented the induction of inflammation and matrix-degradation. Thus, we here provide evidence that our human in vitro 3D OTM mimics cytokine-induced cell- and matrix-related changes-key features of RA-and may serve as a preclinical tool for the evaluation of both new targets and potential drugs in a more translational setup.

6.
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.

8.
Z Rheumatol ; 2020 Nov 16.
Artigo em Alemão | MEDLINE | ID: mdl-33196862

RESUMO

We report the case of a 42-year-old male patient with acute onset of asymmetrical polyarthritis of the medium and large joints as well as fever and elevated serological inflammation markers. The symptoms began shortly after initiation of thiamazole treatment for newly diagnosed Graves' disease. Antithyroid arthritis syndrome (AAS) is a rare but serious adverse side effect of antithyroid treatment with thioamides such as thiamazole. Clinically, AAS may present with myalgia, arthralgia, fever, exanthema and polyarthritis. In the case of suspected AAS, when possible the thionamide medication should be rapidly discontinued or modified in consultation with the endocrinologist. In some cases anti-inflammatory therapy with NSAID or corticosteroids may be required for symptom control.

9.
J Am Geriatr Soc ; 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33075140

RESUMO

OBJECTIVE: To identify barriers and solutions for the recruitment and retention of older (aged ≥65 years) people in clinical trials. DESIGN: Systematic literature review. METHODS: Three databases (Medline, Embase, and CENTRAL) were searched for articles reporting on barriers or solutions regarding the recruitment or retention of older people. Only original research articles were included. RESULTS: Fifty eligible articles were identified. Exclusion criteria were the most common cause of poor recruitment of older adults (mainly age and comorbidities). Patients' families or physicians often advised against participation (22% of included studies). Lack of interest (18%) and problems with transportation (18%) were also commonly cited as challenges. Fourteen trials (28%) reported that monitoring and adapting their recruitment methods helped, along with a flexible research team (26%) and provision of transportation (24%). Retention was impaired by death (12%), illness (8%), and loss of interest (6%). Methods with a positive effect on retention included financial incentives and regular information about the progress of the study (12%), a low staff turnover (12%), flexibility in appointment making (10%), and expression of appreciation by the staff through letters, gifts, and cards to the participants (10%). CONCLUSION: We identified several barriers and have listed potential solutions that may improve recruitment and lead to fewer dropouts in trials involving older populations. Implementation of our findings may help mitigate the manifold challenges that come with running a trial with older people.

10.
Clin Rheumatol ; 39(12): 3535-3541, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33067772

RESUMO

The novel coronavirus disease (COVID-19) pandemic has significantly impacted the field of rheumatology, in both the delivery of clinical care and didactic education for our trainees. These changes have generated significant strain for program directors and clinical educators who have had to leverage technology and develop new systems to ensure continued trainee education and assessment. We aim to outline the impacts on formal education programs presented by these unprecedented disruptions, describe the development and deployment of online teaching, reflect on the challenges and opportunities for technology-enabled learning and use of social media for education, and give some international perspectives on impacts on postgraduate rheumatology training outside the USA. With the rapid dissolution of barriers in place during the pre-COVID-19 era, we have the opportunity to assess the efficacy of new methods of care and further integrate technology into teaching and assessment. We propose that a hybrid in-person and technology-enabled learning approach, so-called blended learning, is likely to remain the most desirable future model for supporting trainee learning.


Assuntos
Infecções por Coronavirus/epidemiologia , Educação a Distância/métodos , Educação de Pós-Graduação em Medicina/métodos , Pneumonia Viral/epidemiologia , Reumatologia/educação , Currículo , Humanos , Disseminação de Informação , Pandemias , Mídias Sociais
11.
Curr Rheumatol Rep ; 22(12): 85, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33047263

RESUMO

PURPOSE: While glucocorticoids (GCs) are effective in large vessel vasculitis (LVV), they may cause serious adverse events (AEs), especially if taken for longer durations and at higher doses. Unfortunately, patients suffering from LVV often need long-term treatment with GCs; therefore, toxicity needs to be expected and countered. RECENT FINDINGS: GCs remain the mainstay of therapy for both giant cell arteritis and Takayasu arteritis. In order to minimize their toxicity, the following strategies should be considered: GC tapering, administration of conventional synthetic (e.g., methotrexate) or biologic (e.g., tocilizumab) GC-sparing agents, as well as monitoring, prophylaxis, and treatment of GC-related AEs. Several drugs are currently under investigation to expand the armamentarium for the treatment of LVV. GC treatment in LVV is effective but associated with toxicity. Strategies to minimize this toxicity should be applied when treating patients suffering from LVV.

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.

14.
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.
J Clin Epidemiol ; 127: 151-160, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32781113

RESUMO

OBJECTIVES: The Patient-Reported Outcomes Measurement Information System (PROMIS) physical function (PF) item bank has been developed to standardize patient-reported PF across medical fields. However, evidence of scoring equivalence across cardiology and rheumatology patients is still missing. Therefore, this study aims to investigate both (1) the extent of disease-related differential item functioning (DIF) and (2) the impact of the disease group on using subdomain-specific item sets for generating PROMIS PF scores in cardiology and rheumatology patients. STUDY DESIGN AND SETTING: Ordinal regression was used to evaluate DIF between cardiology (n = 201) and rheumatology (n = 200) inpatients. To explore the disease-specific impact of PF subdomains on scoring, we compared scores derived from the full item bank with scores derived from subdomain-specific item sets for each disease group. RESULTS: DIF was detected in 18 items, predominately from the upper extremity subdomain. When upper extremity items were used, cardiology patients reached systematically higher scores than using the full item bank. Rheumatology patients scored substantially higher when mobility items were used. CONCLUSION: Applying the PROMIS PF metric to disease-specific item sets including items from differing subdomains may lead to biased comparisons of PF levels across disease groups. Disease-specific item parameters should be provided for items showing DIF, and subdomain-related content balancing is recommended for scoring the generic PROMIS PF construct.

17.
Lancet ; 396(10246): 267-276, 2020 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-32711802

RESUMO

BACKGROUND: Patients with inflammatory diseases, such as rheumatoid arthritis, often receive glucocorticoids, but long-term use can produce adverse effects. Evidence from randomised controlled trials to guide tapering of oral glucocorticoids is scarce. We investigated a scheme for tapering oral glucocorticoids compared with continuing low-dose oral glucocorticoids in patients with rheumatoid arthritis. METHODS: The Steroid EliMination In Rheumatoid Arthritis (SEMIRA) trial was a double-blind, multicentre, two parallel-arm, randomised controlled trial done at 39 centres from six countries (France, Germany, Italy, Russia, Serbia, and Tunisia). Adult patients with rheumatoid arthritis receiving tocilizumab and glucocorticoids 5-15 mg per day for 24 weeks or more were eligible for inclusion if they had received prednisone 5 mg per day for 4 weeks or more and had stable low disease activaity, confirmed by a Disease Activity Score for 28 joints-erythrocyte sedimentation rate (DAS28-ESR) of 3·2 or less 4-6 weeks before and on the day of randomisation. Patients were randomly assigned 1:1 to either continue masked prednisone 5 mg per day for 24 weeks or to taper masked prednisone reaching 0 mg per day at week 16. All patients received tocilizumab (162 mg subcutaneously every week or 8 mg/kg intravenously every 4 weeks) with or without csDMARDs maintained at stable doses during the entire 24-week study. The primary outcome was the difference in mean DAS28-ESR change from baseline to week 24, with a difference of more than 0·6 defined as clinically relevant between the continued-prednisone group and the tapered-prednisone group. The trial is registered with ClinicalTrials.gov, NCT02573012. FINDINGS: Between Oct 21, 2015, and June 9, 2017, 421 patients were screened and 259 (200 [77%] women and 59 [23%] men) were recruited onto the trial. In all 128 patients assigned to the continued-prednisone regimen, disease activity control was superior to that in all 131 patients assigned to the tapered-prednisone regimen; the estimated mean change in DAS28-ESR from baseline to week 24 was 0·54 (95% CI 0·35-0·73) with tapered prednisone and -0·08 (-0·27 to 0·12) with continued prednisone (difference 0·61 [0·35-0·88]; p<0·0001), favouring continuing prednisone 5 mg per day for 24 weeks. Treatment was regarded as successful (defined as low disease activity at week 24, plus absence of rheumatoid arthritis flare for 24 weeks and no confirmed adrenal insufficiency) in 99 (77%) patients in the continued-prednisone group versus 85 (65%) patients in the tapered-prednisone group (relative risk 0·83; 95% CI 0·71-0·97). Serious adverse events occurred in seven (5%) patients in the tapered-prednisone group and four (3%) patients in the continued-prednisone group; no patients had symptomatic adrenal insufficiency. INTERPRETATION: In patients who achieved low disease activity with tocilizumab and at least 24 weeks of glucocorticoid treatment, continuing glucocorticoids at 5 mg per day for 24 weeks provided safe and better disease control than tapering glucocorticoids, although two-thirds of patients were able to safely taper their glucocorticoid dose. FUNDING: F Hoffmann-La Roche.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Glucocorticoides/uso terapêutico , Prednisona/uso terapêutico , Indução de Remissão/métodos , Administração Intravenosa , Administração Oral , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Reumatoide/etnologia , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , França/epidemiologia , Alemanha/epidemiologia , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Humanos , Injeções Subcutâneas , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Federação Russa/epidemiologia , Sérvia/epidemiologia , Tunísia/epidemiologia
18.
ALTEX ; 37(4): 561-578, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32521037

RESUMO

The aim of the study was to establish an in vitro fracture hematoma (FH) model that mimics the in vivo situation of the human fracture gap in order to assess drug efficacy and effectiveness for the treatment of fracture healing disorders. Human peripheral blood and mesenchymal stromal cells (MSCs) were coagulated to produce in vitro FH models, which were incubated in osteogenic medium under normoxia/hypoxia and analyzed for cell composition, gene expression and cytokine/chemokine secretion. To evaluate the model, we studied the impact of dexamethasone (impairing fracture healing) and deferoxamine (promoting fracture healing). Under hypoxic conditions, MSCs represented the predominant cell population, while the frequencies of leukocyte populations decreased. Marker gene expression of osteogenesis, angiogenesis, inflammation, migration and hypoxic adaptation increased significantly over time and compared to normoxia, while cytokine/chemokine secretion remained unchanged. Dexamethasone favored the frequency of immune cells compared to MSCs, suppressed osteogenic and pro-angiogenic gene expression, and enhanced the secretion of inflammatory cytokines. Conversely, deferoxamine favored the frequency of MSCs over that of immune cells and enhanced the expression of the osteogenic marker RUNX2 and markers of hypoxic adaptation. In summary, we demonstrate that hypoxia is an important factor for modeling the initial phase of fracture healing in vitro and that both fracture-healing disrupting and promoting substances can influence the in vitro model comparable to the in vivo situation. Therefore, we conclude that our model is able to mimic in part the human FH and could reduce the number of animal experiments in early preclinical studies.

19.
United European Gastroenterol J ; 8(6): 637-666, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32552502

RESUMO

The overall objective of these guidelines is to provide evidence-based recommendations for the diagnosis and management of immunoglobulin G4 (IgG4)-related digestive disease in adults and children. IgG4-related digestive disease can be diagnosed only with a comprehensive work-up that includes histology, organ morphology at imaging, serology, search for other organ involvement, and response to glucocorticoid treatment. Indications for treatment are symptomatic patients with obstructive jaundice, abdominal pain, posterior pancreatic pain, and involvement of extra-pancreatic digestive organs, including IgG4-related cholangitis. Treatment with glucocorticoids should be weight-based and initiated at a dose of 0.6-0.8 mg/kg body weight/day orally (typical starting dose 30-40 mg/day prednisone equivalent) for 1 month to induce remission and then be tapered within two additional months. Response to initial treatment should be assessed at week 2-4 with clinical, biochemical and morphological markers. Maintenance treatment with glucocorticoids should be considered in multi-organ disease or history of relapse. If there is no change in disease activity and burden within 3 months, the diagnosis should be reconsidered. If the disease relapsed during the 3 months of treatment, immunosuppressive drugs should be added.

20.
Biofabrication ; 12(4): 045016, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32598334

RESUMO

Understanding the pathophysiological processes of cartilage degradation requires adequate model systems to develop therapeutic strategies towards osteoarthritis (OA). Although different in vitro or in vivo models have been described, further comprehensive approaches are needed to study specific disease aspects. This study aimed to combine in vitro and in silico modeling based on a tissue-engineering approach using mesenchymal condensation to mimic cytokine-induced cellular and matrix-related changes during cartilage degradation. Thus, scaffold-free cartilage-like constructs (SFCCs) were produced based on self-organization of mesenchymal stromal cells (mesenchymal condensation) and (i) characterized regarding their cellular and matrix composition or secondly (ii) treated with interleukin-1ß (IL-1ß) and tumor necrosis factor α (TNFα) for 3 weeks to simulate OA-related matrix degradation. In addition, an existing mathematical model based on partial differential equations was optimized and transferred to the underlying settings to simulate the distribution of IL-1ß, type II collagen degradation and cell number reduction. By combining in vitro and in silico methods, we aimed to develop a valid, efficient alternative approach to examine and predict disease progression and effects of new therapeutics.

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