Plant-derived pectin nanocoatings to prevent inflammatory cellular response of osteoblasts following Porphyromonas gingivalis infection

Background: Bioengineered plant-derived Rhamnogalacturonan-Is (RG-Is) from pectins are potential candidates for surface nanocoating of medical devices. It has recently been reported that RG-I nanocoatings may prevent bacterial infection and improve the biocompatibility of implants. The aim of the study was to evaluate in vitro impact of bioengineered RG-I nanocoatings on osteogenic capacity and proinflammatory cytokine response of murine osteoblasts following Porphyromonas gingivalis infection. Methods: Murine MC3T3-E1 osteoblasts and isolated primary calvarial osteoblasts from C57BL/6J (B6J osteoblasts) mice were infected with P. gingivalis and incubated on tissue culture polystyrene plates with or without nanocoatings of unmodified RG-Is isolated from potato pulps (PU) or dearabinanated RG-Is (PA). To investigate a behavior of infected osteoblasts cultured on RG-Is cell morphology, proliferation, metabolic activity, mineralization and osteogenic and pro-inflammatory gene expression were examined. Results: Following P. gingivalis infection, PA, but not PU, significantly promoted MC3T3-E1 and BJ6 osteoblasts proliferation, metabolic activity, and calcium deposition. Moreover, Il-1b, Il-6, TNF-α, and Rankl gene expressions were downregulated in cells cultured on PU and to a higher extent on PA as compared to the corresponding control, whereas Runx, Alpl, Col1a1, and Bglap gene expressions were upregulated vice versa. Conclusion: Our data clearly showed that pectin RG-Is nanocoating with high content of galactan (PA) reduces the osteoblastic response to P. gingivalis infection in vitro and may, therefore, reduce a risk of inflammation especially in immunocompromised patients with rheumatoid or periodontal disorders

study protocol for a randomized controlled trial

Background Osteoarthritis (OA) is a heterogeneous group of conditions with disturbed integrity of articular cartilage and changes in the underlying bone. The pathogenesis of OA is multifactorial and not just a disease of older people. Hydroxychloroquine (HCQ) is a disease-modifying anti-rheumatic drug (DMARD) typically used for the treatment of various rheumatic and dermatologic diseases. Three studies of HCQ in OA, including one abstract and one letter, are available and use a wide variety of outcome measures in small patient populations. Despite initial evidence for good efficacy of HCQ, there has been no randomized, double-blind, and placebo-controlled trial in a larger patient group. In the European League Against Rheumatism (EULAR), evidence-based recommendations for the management of hand OA, HCQ was not included as a therapeutic option because of the current lack of randomized clinical trials. Methods/Design OA TREAT is an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial. A total of 510 subjects with inflammatory and erosive hand OA, according to the classification criteria of the American College of Rheumatology (ACR), with recent X-ray will be recruited across outpatient sites, hospitals and universities in Germany. Patients are randomized 1:1 to active treatment (HCQ 200 to 400 mg per day) or placebo for 52 weeks. Both groups receive standard therapy (non-steroidal anti-inflammatory drugs [NSAID], coxibs) for OA treatment, taken steadily two weeks before enrollment and continued further afterwards. If disease activity increases, the dose of NSAID/coxibs can be increased according to the drug recommendation. The co-primary clinical endpoints are the changes in Australian-Canadian OA Index (AUSCAN, German version) dimensions for pain and hand disability at week 52. The co-primary radiographic endpoint is the radiographic progression from baseline to week 52. A multiple endpoint test and analysis of covariance will be used to compare changes between groups. All analyses will be conducted on an intention-to-treat basis. Discussion The OA TREAT trial will examine the clinical and radiological efficacy and safety of HCQ as a treatment option for inflammatory and erosive OA over 12 months. OA TREAT focuses on erosive hand OA in contrast to other current studies on symptomatic hand OA, for example, HERO [Trials 14:64, 2013]

Sustained Increase of 25-Hydroxyvitamin D Levels in Healthy Young Women during Wintertime after Three Suberythemal UV Irradiations—The MUVY Pilot Study

Objectives Vitamin D (VitD) deficiency is a health problem prevalent not only in the elderly but also in young adults. The primary objective of our observational pilot study “MUVY” (Mood, UVR, Vitamin D in Young women) was to test both the short-term and long-term effects of a series of three suberythemal UV radiation (UVR) exposures on the VitD status and well-being of young healthy women during winter in a repeat measure design. Methods 20 healthy young women (Fitzpatrick skin types I–III, aged 21–25 years) received three full body broad band UVR exposures with an escalating erythemally weighted dose schedule during one week in winter, and completed self-report questionnaires monitoring symptoms of depression (Beck Depression Inventory, BDI) and affective state/well-being (Profile of Mood States, POMS) at baseline and three days after the last UVR exposure. 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured in serum at baseline, and at study days 8, 36 and 50. Results Mean baseline 25(OH)D level was 54.3 nmol/L (standard deviation (s.d.) = 24.1), with seven women having VitD deficient status. Relevant symptoms of depression, as indicated by low BDI total scores (0–8), were absent. After the three UVR exposures the increment of 25(OH)D was an average of 13.9 nmol/L (95% confidence interval (CI) = 9.4–18.4) and 26.2 pmol/L (95%CI = 7.2–45.1) for 1,25(OH)2D. Δ25(OH)D, and corresponding baseline levels were significantly and inversely associated (rho = -0.493, p = 0.027). Only 25(OH)D remained significantly increased above baseline for at least six weeks after the last UVR exposure. A strong inverse correlation of the POMS subscale “Vigor/Activity” and the increment in 1,25(OH)2D was found (rho = -0.739, p<0.001) at day 8. Conclusions Three suberythemal whole body UVR exposures during one week are a simple and suitable method for improving 25(OH)D levels during winter, for at least six weeks, and especially in young women with VitD deficient status. Trial Registration German Clinical Trials Register (Deutsches Register Kinischer Studien) DRKS0000927

Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA)

Background: Patients with rheumatoid arthritis (RA) are at increased risk of developing comorbid conditions.&lt;p&gt;&lt;/p&gt; Objectives: To evaluate the prevalence of comorbidities and compare their management in RA patients from different countries worldwide.&lt;p&gt;&lt;/p&gt; Methods Study design: international, cross-sectional. Patients: consecutive RA patients. Data collected: demographics, disease characteristics (activity, severity, treatment), comorbidities (cardiovascular, infections, cancer, gastrointestinal, pulmonary, osteoporosis and psychiatric disorders).&lt;p&gt;&lt;/p&gt; Results: Of 4586 patients recruited in 17 participating countries, 3920 were analysed (age, 56±13 years; disease duration, 10±9 years (mean±SD); female gender, 82%; DAS28 (Disease Activity Score using 28 joints)–erythrocyte sedimentation rate, 3.7±1.6 (mean±SD); Health Assessment Questionnaire, 1.0±0.7 (mean±SD); past or current methotrexate use, 89%; past or current use of biological agents, 39%. The most frequently associated diseases (past or current) were: depression, 15%; asthma, 6.6%; cardiovascular events (myocardial infarction, stroke), 6%; solid malignancies (excluding basal cell carcinoma), 4.5%; chronic obstructive pulmonary disease, 3.5%. High intercountry variability was observed for both the prevalence of comorbidities and the proportion of subjects complying with recommendations for preventing and managing comorbidities. The systematic evaluation of comorbidities in this study detected abnormalities in vital signs, such as elevated blood pressure in 11.2%, and identified conditions that manifest as laboratory test abnormalities, such as hyperglycaemia in 3.3% and hyperlipidaemia in 8.3%.&lt;p&gt;&lt;/p&gt; Conclusions: Among RA patients, there is a high prevalence of comorbidities and their risk factors. In this multinational sample, variability among countries was wide, not only in prevalence but also in compliance with recommendations for preventing and managing these comorbidities. Systematic measurement of vital signs and laboratory testing detects otherwise unrecognised comorbid conditions.&lt;p&gt;&lt;/p&gt

The association between rheumatoid arthritis and periodontal disease

Chronic, plaque-associated inflammation of the gingiva and the periodontium are among the most common oral diseases. Periodontitis (PD) is characterized by the inflammatory destruction of the periodontal attachment and alveolar bone, and its clinical appearance can be influenced by congenital as well as acquired factors. The existence of a rheumatic or other inflammatory systemic disease may promote PD in both its emergence and progress. However, there is evidence that PD maintains systemic diseases. Nevertheless, many mechanisms in the pathogenesis have not yet been examined sufficiently, so that a final explanatory model is still under discussion, and we hereby present arguments in favor of this. In this review, we also discuss in detail the fact that oral bacterial infections and inflammation seem to be linked directly to the etiopathogenesis of rheumatoid arthritis (RA). There are findings that support the hypothesis that oral infections play a role in RA pathogenesis. Of special importance are the impact of periodontal pathogens, such as Porphyromonas gingivalis on citrullination, and the association of PD in RA patients with seropositivity toward rheumatoid factor and the anti-cyclic citrullinated peptide antibody

Rheumatoid arthritis - clinical aspects: 134. Predictors of Joint Damage in South Africans with Rheumatoid Arthritis

Background: Rheumatoid arthritis (RA) causes progressive joint damage and functional disability. Studies on factors affecting joint damage as clinical outcome are lacking in Africa. The aim of the present study was to identify predictors of joint damage in adult South Africans with established RA. Methods: A cross-sectional study of 100 black patients with RA of >5 years were assessed for joint damage using a validated clinical method, the RA articular damage (RAAD) score. Potential predictors of joint damage that were documented included socio-demographics, smoking, body mass index (BMI), disease duration, delay in disease modifying antirheumatic drug (DMARD) initiation, global disease activity as measured by the disease activity score (DAS28), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and autoantibody status. The predictive value of variables was assessed by univariate and stepwise multivariate regression analyses. A p value <0.05 was considered significant. Results: The mean (SD) age was 56 (9.8) years, disease duration 17.5 (8.5) years, educational level 7.5 (3.5) years and DMARD lag was 9 (8.8) years. Female to male ratio was 10:1. The mean (SD) DAS28 was 4.9 (1.5) and total RAAD score was 28.3 (12.8). The mean (SD) BMI was 27.2 kg/m2 (6.2) and 93% of patients were rheumatoid factor (RF) positive. More than 90% of patients received between 2 to 3 DMARDs. Significant univariate predictors of a poor RAAD score were increasing age (p = 0.001), lower education level (p = 0.019), longer disease duration (p < 0.001), longer DMARD lag (p = 0.014), lower BMI (p = 0.025), high RF titre (p < 0.001) and high ESR (p = 0.008). The multivariate regression analysis showed that the only independent significant predictors of a higher mean RAAD score were older age at disease onset (p = 0.04), disease duration (p < 0.001) and RF titre (p < 0.001). There was also a negative association between BMI and the mean total RAAD score (p = 0.049). Conclusions: Patients with longstanding established RA have more severe irreversible joint damage as measured by the clinical RAAD score, contrary to other studies in Africa. This is largely reflected by a delay in the initiation of early effective treatment. Independent of disease duration, older age at disease onset and a higher RF titre are strongly associated with more joint damage. The inverse association between BMI and articular damage in RA has been observed in several studies using radiographic damage scores. The mechanisms underlying this paradoxical association are still widely unknown but adipokines have recently been suggested to play a role. Disclosure statement: C.I. has received a research grant from the Connective Tissue Diseases Research Fund, University of the Witwatersrand. All other authors have declared no conflicts of interes

Strategies for prognostic improvement in patients with rheumatoid arthritis

Das Management der Rheumatoiden Arthritis (RA) zeigt inzwischen gerade auf medikamentösem Gebiet gute Erfolge für den Patienten, so dass die Krankheitsaktivität, die Funktion und die Lebensqualität der Patienten mit Hilfe zahlreicher Therapiestrategien deutlich verbessert werden konnten. Das Treat-to target-Konzept (T2T) fasst die Erkenntnisse der vergangenen Jahre, die weltweit publiziert wurden, in einer Empfehlung zu einem interdisziplinären RA-Management unter direktem Einbezug des Patienten zusammen. Inzwischen sind Behandlungserfolge in allen RA-Erkrankungsstadien erreichbar. Zunehmend geht es um die Verbesserung der Versorgung durch eine bessere Früherkennung und eine optimale Behandlungsstrategie, wie beispielsweise die frühe Induktionstherapie in der Frühphase der Erkrankung bzw. inzwischen sogar noch vor Manifestation des vollständigen Erkrankungsbildes. Darüber hinaus wurde erkannt, dass zahlreiche Komorbiditäten bei RA-Patienten im Hinblick auf die Mortalität eine große Rolle spielen und deren Erkennung als auch Überwachung beim RA-Patienten noch deutlichen Versorgungsdefiziten unterworfen ist. So können zahlreiche Maßnahmen, um Komorbiditäten zu kontrollieren und zu reduzieren, sowohl von anderen chronischen Erkrankungen übernommen werden, andere Strategien müssen unter dem Blickwinkel der entzündlichen Autoimmunerkrankung festgelegt werden bzw. in ihren Assoziationen der Erkrankungen weiter erforscht werden. Die Habilitationsschrift vermittelt einen Überblick zu ausgewählten T2T- Schwerpunkten, wie 1. das Konzept des „window of opportunity“ mit der Darstellung der Ergebnisse der Therapieinduktion in der Frühphase der RA in der durch das Bundesministerium für Bildung und Forschung geförderten HIT HARD-Studie (ISRCTN36745608; EudraCT-Number: 2006-003146-41.), 2\. Ergebnisse zu Prävalenzuntersuchungen von Komorbiditäten bei RA und ersten Schlussfolgerungen im inter- und transdisziplinären Management der Komorbiditäten, 3\. Studienergebnisse zu beispielhaft ausgewählten Komorbiditäten der RA mit dem Ziel, Wege der verbesserten Diagnostik und Versorgung der Komorbiditäten zu finden. Folgende Schlussfolgerungen können aus der Auswahl der in dieser Habilitationsschrift zugrunde gelegten Forschungsergebnisse zusammenfassend dargelegt werden: 1\. Die frühe Identifizierung der RA-Patienten und daran gebundenen frühen intensiven Therapieeinleitung führt bei einem großen Anteil von Patienten zu einem schnellen Therapieansprechen mit positiven Auswirkungen auf die Lebensqualität ermittelt am SF-36-Score und auf den HAQ-DI ermittelten Funktionsstatus. Eine Kombination der MTX-Basistherapie mit einem Biologikum ermöglicht bei der Mehrzahl der Patienten das Erreichen einer Remission bzw. einer niedrigmöglichen Krankheitsaktivität (low disease activity, LDA), sowie eine prognostische Verbesserung im radiologischen Verlauf. 2\. Die RA-Erkrankung wird in ihrem Verlauf nicht nur von der Erkrankung selbst, sondern auch von der Diagnostik und adäquaten Behandlung der Komorbiditäten bestimmt. 3\. Die Diagnostik und Behandlung der Komorbiditäten erfordert ein inter- und transdisziplinäres Management zwischen den einzelnen Fachdisziplinären und Akteuren der rheumatologischen Versorgung. 4\. Fatigue wird häufig mit Schlafstörungen verbunden, die sich möglicherweise in einzelnen Schlafphasen nachweisen lassen. Weitere Studien dazu sind künftig erforderlich. Therapien, so auch antirheumatische Basis- und Biologikatherapien können die Schlafeffizienz der RA-Patienten verbessern und wirken sich im Zusammenspiel der pro- und inflammatorischen Zytokinwirkungen auf den Entzündungs- und Schmerzprozess aus, die in weiteren Studien spezifiziert werden müssen. 5\. Die Parodontitis hat als Entzündungsfokus Auswirkungen auf die RA-Erkrankung. Aber auch die RA-Erkrankung beeinflusst die Parodontitis. Es liegt insbesondere bei RA-Patienten als auch bei Patienten mit einer ankylosierenden Spondyloarthritis und Patienten mit einer Systemischen Sklerose ein erhöhtes Risiko für die Entwicklung einer Parodontitis mit der Folge eines erhöhten Attachementverlustes vor. Präventionsmaßnahmen, aber auch effiziente Diagnostik und Behandlung der Parodontitis sollten im inter- und transdisziplinären Management der rheumatischen Erkrankungen berücksichtigt werden. 6\. Der Vitamin D-Mangel ist im Auftreten sowohl national als auch weltweit in der Bevölkerung sehr häufig mit Auswirkungen auf den Knochenstoffwechsel, psychischen Stimmungsveränderungen und zahlreichen anderen metabolisch verursachten Störungen als Folge. Neben der Supplementation ist die Induktion des natürlichen Vitamin D-Syntheseprozesses über die Haut eine effiziente Methode, um den 25-Hydroxy-Vitamin D3-Spiegel zu erhöhen und zu stabilisieren. Eine dreimalige UV-Applikationen unterhalb der individuell definierten und vom jeweiligen Hauttyp abhängigen Erythemschwelle zeigen bei gesunden, jungen Probandinnen einen signifikanten Effekt auf die Steigerung des 25-Hydroxy-Vitamin D3- Spiegels über mehrere Tage anhaltend. Darüber hinaus zeigten sich tendenzielle Effekte auf die Stimmung der Probandinnen. Weitere Studien an Patienten sind nachfolgend zur Untersuchung, ob sich diese Ergebnisse auf die verschiedenen Erkrankungsbilder übertragen lassen, erforderlich. 7\. Klinisch orientierte Versorgungsstudien sind wichtiger Bestandteil funktionierender Gesundheitssysteme und Basis der universitären Forschung, um relevante Fragestellungen des diagnostischen und therapeutischen Alltags und der Patientenperspektive zu beantworten und in Form von evidencebasierten Handlungsempfehlungen konkret umzusetzen als auch stetig im Erfolg zu überprüfen.The management of rheumatoid arthritis (RA) has now shown good results for the patient, especially in the area of medication, so that the patient's disease activity, function and quality of life are significantly improved by means of numerous therapies could become. The published worldwide treat-to-target- concept (T2T) summarizes the findings of the past years in a recommendation to an interdisciplinary RA management with direct involvement of the patient. In the meantime, treatment success is achievable at all RA disease stages. Increasingly, care is being improved by means of better early detection and an optimal treatment strategy, such as early induction therapy in the early phase of the disease or even before the manifestation of the complete picture of the disease. In addition, it was recognized that numerous comorbidities in RA patients with regard to mortality play a major role and their detection and monitoring are still subject to significant deficits in the RA patient. Thus, numerous measures to control and reduce comorbidities can be taken over by other chronic diseases; other strategies must be defined under the angle of inflammatory autoimmune disease, or further investigated in their associations of diseases. This work provide an overview of selected T2T centers such as 1\. the concept of the "window of opportunity" with the presentation of the results of the therapy induction in the early phase of the RA in the HIT HARD study funded by the German Federal Ministry of Education and Research (ISRCTN36745608, EudraCT-Number: 2006-003146-41), 2\. results on prevalence studies of comorbidities in RA and first conclusions in inter- and transdisciplinary management of comorbidities, 3\. study results on exemplary comorbidities of RA with the aim of finding ways of improved diagnosis and care for comorbidities. The following conclusions can be summarized from the selection of the research results used in this work: 1\. The early identification of RA patients and the early intensive initiation of therapy, which is linked to this, leads to a rapid response to therapy with a positive effect on the quality of life determined by the SF-36 score in a large proportion of patients and the function status determined on the HAQ-DI. A combination of MTX therapy with a biologic enables the majority of patients to achieve a response or a low disease activity (LDA) as well as a prognostic improvement in the radiological outcome. 2\. RA disease is determined not only by the disease itself, but also by the diagnosis and adequate treatment of the comorbidities. 3\. The diagnosis and treatment of comorbidities requires an interdisciplinary and transdisciplinary management between the various specialist disciplines and rheumatologic care providers. 3\. The diagnosis and treatment of comorbidities requires an interdisciplinary and transdisciplinary management between the various specialist disciplines and rheumatologic care providers. 4\. Fatigue is often associated with sleep disturbances that may be detected in individual sleep phases. Further studies will be necessary in the future. Therapies, including conventional synthetic and biologic disease modifying therapies, can improve the sleep efficacy of RA patients and interfere with the pro-inflammatory and cytokine effects on the inflammation and pain process, which must be specified in further studies. 5\. Periodontal disease has as an inflammatory focus effects on RA disease. But the RA disease also affects periodontal disease. In RA patients as well as in patients with ankylosing spondyloarthritis and patients with systemic sclerosis, there is an increased risk of the development of periodontal disease with the consequence of increased attachment loss. Prevention measures as well as efficient diagnostics and treatment of periodontal disease should be taken into account in the interdisciplinary and transdisciplinary management of rheumatic diseases. 6\. The vitamin D deficiency is occurring both nationally and globally in the population very frequently with effects on bone metabolism, mental mood changes and numerous other metabolically caused disorders as a result. In addition to supplementation, the induction of the natural vitamin D synthesis process via the skin is an efficient method to increase and stabilize the 25-hydroxy vitamin D3 level. A three-fold UV application below the individually defined erythema threshold, which is dependent on the particular type of skin, shows a significant effect on the increase in the 25-hydroxy vitamin D3 level in healthy young subjects. A three-fold UV application below the individually defined erythema threshold, which is dependent on the particular type of skin, shows a significant effect on the increase in the 25-hydroxy vitamin D3 level over several days in healthy young subjects. In addition, approximate effects on the mood of the subjects were shown. Further studies in patients are subsequently required to determine whether these results can be transferred to the various disease images. 7\. Clinically oriented care studies are an important part of functioning health systems and the basis of university research in order to answer relevant questions of everyday diagnostic and therapeutic practice and the patient's perspective, and to implement them in the form of evidence-based recommendations for action

Induction maintenance with tumour necrosis factor-inhibitor combination therapy with discontinuation versus methotrexate monotherapy in early rheumatoid arthritis: a systematic review and meta-analysis of efficacy in randomised controlled trials

To determine whether an induction-maintenance strategy of combined therapy (methotrexate (MTX)+tumour necrosis factor (TNF) inhibitor (TNFi)) followed by withdrawal of TNFi could yield better long-term results than a strategy with MTX monotherapy, since it is unclear if the benefits from an induction phase with combined therapy are sustained if TNFi is withdrawn. We performed a meta-analysis of trials using the initial combination of MTX+TNFi in conventional synthetic disease-modifying antirheumatic drug-naïve patients with early rheumatoid arthritis (RA). A systematic literature search was performed for induction-maintenance randomised controlled trials (RCTs) where initial combination therapy was compared with MTX monotherapy in patients with clinically active early RA. Our primary outcome was the proportion of patients who achieved low disease activity (LDA; Disease Activity Score (DAS)28 <3.2) and/or remission (DAS28 <2.6) at 12-76 weeks of follow-up. A random-effects model was used to pool the risk ratio (RR) for LDA and remission and heterogeneity was explored by subgroup analyses. We identified 6 published RCTs, 4 of them where MTX+adalimumab was given as initial therapy and where adalimumab was withdrawn in a subset of patients after LDA/remission had been achieved. 2 additional trials used MTX+infliximab as combination therapy. The pooled RRs for achieving LDA and clinical remission at follow-up after withdrawal of TNFi were 1.41 (95% CI 1.05 to 1.89) and 1.34 (95% CI 0.95 to 1.89), respectively. There was significant heterogeneity between trials due to different treatment strategies, which was a limitation to this study. Initial therapy with MTX+TNFi is associated with a higher chance of retaining LDA and/or remission even after discontinuation of TNF