Cohort profile: methodology and cohort characteristics of the Aotearoa New Zealand Rheumatic Heart Disease Registry.

PURPOSE: To create a cohort with high specificity for moderate and severe rheumatic heart disease (RHD) in New Zealand, not reliant on International Classification of Diseases discharge coding. To describe the demography and cardiac profile of this historical and contemporary cohort. DESIGN AND PARTICIPANTS: Retrospective identification of moderate or severe RHD with disease onset by 2019. Case identification from the following data sources: cardiac surgical databases, RHD case series, percutaneous balloon valvuloplasty databases, echocardiography databases, regional rheumatic fever registers and RHD clinic lists. The setting for this study was a high-income country with continued incidence of acute rheumatic fever (ARF). FINDINGS TO DATE: A Registry cohort of 4959 patients was established. The initial presentation was RHD without recognised prior ARF in 41%, and ARF in 59%. Ethnicity breakdown: Maori 38%, Pacific 33.5%, European 21.9%, other 6.7%. Ethnic disparities have changed significantly over time. Prior to 1960, RHD cases were 64.3% European, 25.3% Maori and 6.7% Pacific. However, in contrast, from 2010 to 2019, RHD cases were 10.7% European, 37.4% Maori and 47.2% Pacific.Follow-up showed 32% had changed region of residence within New Zealand from their initial presentation. At least one cardiac intervention (cardiac surgery, transcatheter balloon valvuloplasty) was undertaken in 64% of the cohort at a mean age of 40 years. 19.8% of the cohort had multiple cardiac interventions. At latest follow-up, 26.9% of the cohort died. Of those alive, the mean follow-up is 20.5+19.4 years. Maori and Pacific led governance groups have been established to provide data governance and oversight for the registry. FUTURE PLANS: Detailed mortality and morbidity of the registry cases will be defined by linkage to New Zealand national health data collections. The contemporary cohort of the registry will be available for future studies to improve clinical management and outcomes for the 3450 individuals living with chronic RHD.

Coexistence of acute poststreptococcal glomerulonephritis and acute rheumatic fever in a Japanese girl with primary Sjögren's syndrome.

Although acute poststreptococcal glomerulonephritis (APSGN) and acute rheumatic fever (ARF) are well-known complications of group A streptococcus infection, concomitant occurrence of both diseases is rare. We report an 11-year-old Japanese girl with primary Sjögren's syndrome complicated by acute renal failure about 2 weeks after the onset of pharyngitis. Although histopathological findings of the kidney were not confirmative, APSGN was suggested by the spontaneous recovery of her renal function, typical latent period with high levels of antistreptolysin O and low serum levels of C3 but not of C4. In addition, cardiac hypomotility and regurgitation of the 4 valves progressed in the convalescent phase of APSGN, which was accompanied by elevation of serum C-reactive protein and plasma brain natriuretic peptide (BNP) levels. Myocarditis was suggested by delayed gadolinium-enhancement of cardiac walls on cardiac magnetic resonance imaging. She was diagnosed with APSGN and ARF and was treated with a combination of short course prednisolone and prophylactic penicillin G. There is no relapse of renal or cardiac symptoms during 6 years follow-up. Unexpected elevation of plasma BNP in a convalescent stage of APSGN suggests the development of ARF. Underlying Sjögren's syndrome (SS) may modify the histopathological findings and make it difficult to differentiate APSGN from CTD-associated nephritis such as lupus nephritis (LN) even by renal biopsy.

Computer- and Telephone-Delivered Interventions on Patient Outcomes and Resource Utilization in Patients With Orthopaedic Conditions: A Systematic Review and Narrative Synthesis.

BACKGROUND: As the number of patients with orthopaedic conditions has risen continuously, hospital-based healthcare resources have become limited. Delivery of additional services is needed to adapt to this trend. PURPOSE: The purpose of this study was to describe the current literature of computer- and telephone-delivered interventions on patient outcomes and resource utilization in patients with orthopaedic conditions. METHODS: The systematic review was conducted in January 2019. The standardized checklist for randomized controlled trials was used to assess the quality of the relevant studies. A meta-analysis was not possible due to heterogeneity in the included studies, and a narrative synthesis was conducted to draw informative conclusions relevant to current research, policy, and practice. RESULTS: A total of 1,173 articles were retrieved. Six randomized controlled trials met the inclusion criteria, providing evidence from 434 individuals across four countries. Two studies reported findings of computer-delivered interventions and four reported findings of telephone-delivered interventions. The patients who received both computer- and telephone-delivered interventions showed improvements in patient outcomes that were similar or better to those of patients receiving conventional care. This was without any increase in adverse events or costs. CONCLUSION: Computer- and telephone-delivered interventions are promising and safe alternatives to conventional care. This review, however, identifies a gap in evidence of high-quality studies exploring the effects of computer- and telephone-delivered interventions on patient outcomes and resource utilization. In future, these interventions should be evaluated from the perspective of intervention content, self-management, and patient empowerment. In addition, they should consider the whole care journey and the development of the newest technological innovations. Additionally, future surgery studies should take into account the personalized needs of special, high-risk patient groups and focus on patient-centric care to reduce postdischarge health problems and resource utilization in this population.

A core-shell structure QRu-PLGA-RES-DS NP nanocomposite with photothermal response-induced M2 macrophage polarization for rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is a degenerative joint disease caused by autoimmunity; for the effective treatment of RA while avoiding the side effects of conventional drugs, we have proposed a new therapeutic strategy to eliminate the inflammatory response in RA by regulating the immune system that promotes the transformation of M1-type macrophages to M2-type macrophages. Herein, we designed and synthesized a core-shell nanocomposite (QRu-PLGA-RES-DS NPs), which showed an effective therapeutic effect on RA by accurately inducing the polarization of M2 macrophages. In this system, the quadrilateral ruthenium nanoparticles (QRuNPs) with a photothermal effect were utilized as a core and the thermosensitive molecular poly (lactic-co-glycolic acid) (PLGA) modified with the targeted molecule dextran sulfate (DS) was employed as a shell. Then, the nanocarrier QRu-PLGA-DS NPs effectively improved the water solubility and targeting of resveratrol (RES) through self-assembly. Therefore, the QRu-PLGA-RES-DS NPs significantly enhanced the ability of RES to reverse the M1 type macrophages to the M2 type macrophages through an accurate release. In vivo experiments further demonstrated that the QRu-PLGA-RES-DS NPs could effectively accumulate in the lesion area with an exogenous stimulus, and this significantly enhanced the transformation of the M2 type macrophages and decreased the recruitment of the M1 type macrophages. Furthermore, the QRu-PLGA-RES-DS NPs effectively treated RA by eliminating the inflammatory response; in addition, photoacoustic imaging (PA) of the QRu NPs provided image guidance for the distribution and analysis of nanomedicine in inflammatory tissues. Hence, this therapeutic strategy promotes the biological applications of Ru-based nanoparticles in disease treatment.

Evolutive study of rheumatic carditis cases treated with corticosteroids in a Public Hospital / Estudo evolutivo de casos de cardite reumática tratados com corticosteróides em um hospital público

Background: Rheumatic carditis is a challenge for treatment and secondary prophylaxis, due to severe valve sequelae. Objective: To evaluate the cases of rheumatic carditis in patients under 18 years old treated with corticosteroids.Methods: An observational, longitudinal and retrospective study was carried out on the profile of patients, in the period of 2000-2015. We selected those who received corticosteroid therapy at immunosuppressive doses, for the treatment of carditis and were aged 5 to 18 years. Data were extracted from medical records. Calculations of: averages, standard deviations, medians and interquartile ranges, ratios and 95% confidence intervals were obtained. Chi-square and Wilcoxon tests were applied for comparisons. The level of significance was 5%. Results: Of the 93 cases, 93.53% developed moderate or severe carditis. Mitral regurgitation was detected in 100% of the sample. Pulse therapy was administered in 11.83%. Surgery was performed in 23.69% of patients: mitral, aortic and/or tricuspid valve repair or replacement. The evolution of the cases was favorable in 70.96%. There was a good response among those who received only clinical treatment and those who belonged to the surgical group. The comparison of the initial and posterior valve lesions to the corticoid use was statistically significant (p < 0.001). A difference between the ejection fraction medians was observed (p = 0.048). Hospitalization was required twice or more for 45.16% of the patients. The mortality rate was 5.38%.Conclusions: The patients showed significant clinical improvement. The treatment was effective, reducing trivalvular impairment

Childhood Blastic Plasmacytoid Dendritic Cell Neoplasm Mimicking Acute Rheumatic Fever: Report of an Unusual Clinical Presentation and Review of Literature.

BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is very rarely diagnosed in children with less than 50 cases in the literature. OBSERVATION: We report a case of childhood BPDCN who mimicked acute rheumatic fever at presentation. Majority of the reported childhood BPDCN received acute lymphoblastic leukemia-like chemotherapy with/without stem cell therapy, whereas those who received acute myeloid leukemia-like therapy predominantly succumbed to disease or sepsis. Overall 68% of the patients were alive and achieved complete remission with an overall prognosis slightly better in children compared with adults. CONCLUSIONS: The case is reported due to its unique unusual clinical presentation and its rarity in pediatric population.

Pain management in rheumatology research, training, and practice.

The Pain Management Task Force of the American College of Rheumatology published a report in 2010 highlighting pain management as a fundamental aspect of clinical practice, training and research. In the interim, the consideration of pain as a focus of attention of rheumatologists and rheumatology health professionals has become even more challenging than in 2010 because of the epidemic of opiate addiction and overdose death. The characterisation of categories of pain by mechanism (e.g., inflammation, joint degeneration, abnormalities of central pain processing) can help guide treatment. However, such categorisation can overlook the overlap of these processes and their interaction to create mixed pain states. Further complicating the assessment of pain, outcome measures in rheumatic disease often assess the degree of pain indirectly while concentrating on the quantification of inflammation. Non-inflammatory pain often persists despite treatment, highlighting the need for alternative analgesic therapies. Recommended therapies include acetaminophen, nonsteroidal anti-inflammatory drugs, and stimulators of the pain inhibitory pathway. Each of these non-opioid therapies has incomplete efficacy and potential toxicities that can limit their utility. Non-pharmacologic therapies can show efficacy that rivals or surpasses pharmacologic therapies in the control of pain and improving function in a variety of rheumatic disorders including chronic low back pain and fibromyalgia. A limitation of the use of these therapies is inadequate training and appreciation of their benefits. Furthermore, the supply of trained practitioners to provide non-pharmacological care and support patient efforts for self-management is often limited. Together, these considerations suggest the importance of a renewed effort to implement task force recommendations.

[Regenerative medicine for cartilage defect in rheumatic disease].

Persistent inflammation in rheumatoid arthritis (RA) can lead to the profound degradation and defect of articular cartilage. We can treat or induce the regeneration for the partial cartilage defect using the autologous chondrocytes implantation (ACI) or the matrix-assisted ACI. However, these regenerative methods cannot be applicable for the large size defect due to their limitation of the formable size or available cell numbers. The cell sheet technology or the intra-articular injection technique using the mesenchymal stem cells or the induced pluripotent stem cells (iPS cells) could be applied for the large size cartilage defect in RA patients in the future after additional studies.

Rapid-onset clinical and mechanistic effects of anti-C5aR treatment in the mouse collagen-induced arthritis model.

Preclinical evidence supports targeting the C5a receptor (C5aR) in rheumatoid arthritis (RA). To support ongoing clinical development of an anti-C5aR monoclonal antibody, we have investigated for the first time the mechanism of action and the pharmacodynamics of a blocking anti-murine C5aR (anti-mC5aR) surrogate antibody in mouse collagen-induced arthritis (CIA). First, efficacy was demonstrated in a multiple-dose treatment study. Almost complete inhibition of clinical disease progression was obtained, including reduced bone and cartilage destruction in anti-mC5aR-treated mice. Then, the mechanism of action was examined by looking for early effects of anti-mC5aR treatment in single-dose treatment studies. We found that 48 h after single-dose treatment with anti-mC5aR, the neutrophil and macrophage infiltration into the paws was already reduced. In addition, several inflammatory markers, including tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-17A were reduced locally in the paws, indicating reduction of local inflammation. Furthermore, dose-setting experiments supported a beneficial clinical effect of dosing above the C5aR saturation level. In conclusion, these preclinical data demonstrated rapid onset effects of antibody blockade of C5aR. The data have translational value in supporting the Novo Nordisk clinical trials of an anti-C5aR antibody in rheumatoid arthritis patients, by identifying potential biomarkers of treatment effects as well as by providing information on pharmacodynamics and novel insights into the mechanism of action of monoclonal antibody blockade of C5aR.

Novel insights into the biology of interleukin-32.

Interleukin (IL)-32 is known as a proinflammatory cytokine that is likely involved in several diseases, including infections, chronic inflammation, and cancer. Since the first report in 2005, IL-32 has been the subject of numerous studies to unravel the biological function of this molecule. For example, silencing of endogenous IL-32 in primary or cell lines of human origin consistently suppressed responses to Toll-like receptors. The protein folding structure of the six isoforms of IL-32 does not resemble that of any classical cytokine and as of this writing, a specific IL-32 receptor has not been identified. Instead, we propose a mechanism by which exposure to extracellular IL-32 or overexpression of the molecule results in binding to intracellular partners that influences functions such as gene expression, cell death, or survival. As such, this review offers insights into the role of IL-32 in several diseases, host defense, inflammation, immune function, and cancer. Finally, possibilities to target IL-32 in several diseases are proposed.

[Whipple disease revealed by anti-TNFα therapy]. / Maladie de Whipple révélée par les traitements anti-TNFα

INTRODUCTION: Whipple disease is a rare infectious disease with protean clinical manifestations. This infection may mimic chronic inflammatory rheumatisms such as rheumatoid arthritis or spondylarthritis. In this context, introduction of a biotherapy after a diagnostic hesitation does not always lead to early complications. Sometimes, the clinical degradation follows an initial improvement, encouraging continuation of the immunosuppressive treatment and leading consequently to a greater diagnostic delay. CASE REPORTS: We report two cases of Whipple disease diagnosed in the context of an inflammatory disease with anti-TNFα failure. The first patient was a 53-year-old man who presented with an axial and peripheral spondylarthritis who was treated with etanercept and adalimumab. The second was a 42-year-old man who received adalimumab and then etanercept for a peripheral spondylarthritis. CONCLUSION: Whipple disease should be suspected in all patients who present with a chronic inflammatory rheumatism that is partially or not controlled with anti-TNFα therapy and who had persisting elevated acute phase reactants.

Adams-Stokes attack as the first symptom of acute rheumatic fever: report of an adolescent case and review of the literature.

BACKGROUND: Acquired complete heart block, in pediatric age is mainly the results of direct injury to conduction tissue during cardiac surgery or cardiac catheterisation. It can also be observed in different clinical settings as infectious diseases, neoplasia, and inflammatory diseases. It has a wide range of presentation and in some settings it can appear a dramatic event. Although a rare finding during acute rheumatic fever, with a transient course, it may need a specific and intensive treatment. CASE PRESENTATION: We report the case of an Adams-Stokes attack in an adolescent with acute rheumatic carditis and complete atrio-ventricular block. The attack was the first symptom of carditis.We reviewed the literature and could find 25 cases of complete atrio-ventricular block due to rheumatic fever. Ten of the 25 patients experienced an Adams-Stokes attack. Nineteen of the 25 patients were certainly in the pediatric age group. Seven of the 19 pediatric cases experienced an Adams-Stokes attack. In 16/25 cases, the duration of the atrio-ventricular block was reported: it lasted from a few minutes to ten days. Pacemaker implantation was necessary in 7 cases. CONCLUSION: Rheumatic fever must be kept in mind in the diagnostic work-up of patients with acquired complete atrio-ventricular block, particularly when it occurs in pediatric patients. The insertion of a temporary pacemaker should be considered when complete atrio-ventricular block determines Adams-Stokes attacks. Complete heart block during acute rheumatic fever is rare and is usually transient. Along with endocarditis, myocarditis and pericarditis, complete atrio-ventricular block has been recognized, rarely, during the course of acute rheumatic carditis.

Acute rheumatic fever and rheumatic heart disease--priorities in prevention, diagnosis and management. A report of the CSANZ Indigenous Cardiovascular Health Conference, Alice Springs 2011.

Three priority areas in the prevention, diagnosis and management of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) were identified and discussed in detail: 1. Echocardiography and screening/diagnosis of RHD ­ Given the existing uncertainty it remains premature to advocate for or to incorporate echocardiographic screening for RHD into Australian clinical practice. Further research is currently being undertaken to evaluate the potential for echocardiography screening. 2. Secondary prophylaxis ­ Secondary prophylaxis (long acting benzathine penicillin injections) must be seen as a priority. Systems-based approaches are necessary with a focus on the development and evaluation of primary health care-based or led strategies incorporating effective health information management systems. Better/novel systems of delivery of prophylactic medications should be investigated. 3. Management of advanced RHD ­ National centres of excellence for the diagnosis, assessment and surgical management of RHD are required. Early referral for surgical input is necessary with multidisciplinary care and team-based decision making that includes patient, family, and local health providers. There is a need for a national RHD surgical register and research strategy for the assessment, intervention and long-term outcome of surgery and other interventions for RHD.

Human mesenchymal stem cells inhibit osteoclastogenesis through osteoprotegerin production.

OBJECTIVE: Mesenchymal stem cells (MSCs) have been proposed to be a useful tool for treatment of rheumatoid arthritis (RA), not only because of their multipotency but also because of their immunosuppressive effect on lymphocytes, dendritic cells, and other proinflammatory cells. Since bone destruction caused by activated osteoclasts occurs in RA, we undertook the present study to investigate the effect of MSCs on osteoclast function and differentiation in order to evaluate their potential use in RA therapy. METHODS: Human MSCs and peripheral blood mononuclear cells were cultured under cell-cell contact-free conditions with osteoclast induction medium. Differentiation into osteoclast-like cells was determined by tartrate-resistant acid phosphatase staining and expression of osteoclast differentiation markers. RESULTS: The number of osteoclast-like cells was decreased and expression of cathepsin K and nuclear factor of activated T cells c1 (NF-ATc1) was down-regulated by the addition of either MSCs or a conditioned medium obtained from MSCs. Osteoprotegerin (OPG) was constitutively produced by MSCs and inhibited osteoclastogenesis. However, osteoclast differentiation was not fully recovered upon treatment with either anti-OPG antibody or OPG small interfering RNA, suggesting that OPG had only a partial role in the inhibitory effect of MSCs. Moreover, bone-resorbing activity of osteoclast-like cells was partially recovered by addition of anti-OPG antibody into the conditioned medium. CONCLUSION: The present results indicate that human MSCs constitutively produce OPG, resulting in inhibition of osteoclastogenesis and expression of NF-ATc1 and cathepsin K in the absence of cell-cell contact. Therefore, we conclude that human MSCs exert a suppressive effect on osteoclastogenesis, which may be beneficial in inhibition of joint damage in RA.

Rheumatic heart disease in indigenous populations.

Rates of acute rheumatic fever and chronic rheumatic heart disease in Aboriginal people, Torres Strait Islanders and Maori continue to be unacceptably high. The impact of rheumatic heart disease is inequitable on these populations as compared with other Australians and New Zealanders. The associated cardiac morbidity, including the development of rheumatic valve disease, and cardiomyopathy, with possible sequelae of heart failure, development of atrial fibrillation, systemic embolism, transient ischaemic attacks, strokes, endocarditis, the need for interventions including cardiac surgery, and impaired quality of life, and shortened life expectancy, has major implications for the individual. The adverse health and social effects may significantly limit education and employment opportunities and increase dependency on welfare. Additionally there may be major adverse impacts on family and community life. The costs in financial terms and missed opportunities, including wasted young lives, are substantial. Prevention of acute rheumatic fever is dependent on the timely diagnosis and treatment of sore throats and skin infections in high-risk groups. Both Australia and New Zealand have registries for acute rheumatic fever but paradoxically neither includes all cases of chronic rheumatic heart disease many of whom would benefit from close surveillance and follow-up. In New Zealand and some Australian States there are programs to give secondary prophylaxis with penicillin, but these are not universal. Surgical outcomes for patients with rheumatic valvular disease are better for valve repair than for valve replacement. Special attention to the selection of the appropriate valve surgery and valve choice is required in pregnant women. It may be necessary to have designated surgical units managing Indigenous patients to ensure high rates of surgical repair rather than valve replacement. Surgical guidelines may be helpful. Long-term follow-up of the outcomes of surgery in Indigenous patients with rheumatic heart disease is required. Underpinning these strategies is the need to improve poverty, housing, education and employment. Cultural empathy with mutual trust and respect is essential. Involvement of Indigenous people in decision making, design, and implementation of primary and secondary prevention programs, is mandatory to reduce the unacceptably high rates of rheumatic heart disease.

Febre reumática / Rheumatic fever

Ao final do curso acompanhamos vários casos de febre reumática no HUAP, e decidimos realizar uma breve revisão bibliográfica sobre o tema. Foram levantadas publicações nacionais e internacionais. Dividimos o tema, sob o ponto de vista didático, em 12 capítulos, desde a introdução até o tratamento cirúrgico. Concluímos que a doença, embora frequente vem diminuindo em nosso estado, graças à melhoria no nível primário dos servidores de saúde.