Recommendations for the use of ultrasound in rheumatoid arthritis: literature review and SONAR score experience

Ultrasound (US) has become a useful tool in the detection of early disease, differential diagnosis, guidance of treatment decisions and treatment monitoring of rheumatoid arthritis (RA). In 2008, the Swiss Sonography in Arthritis and Rheumatism (SONAR) group was established to promote the use of US in inflammatory arthritis in clinical practice. A scoring system was developed and taught to a large number of Swiss rheumatologists who already contributed to the Swiss Clinical Quality Management (SCQM) database, a national patient register. This paper intends to give a Swiss consensus about best clinical practice recommendations for the use of US in RA on the basis of the current literature knowledge and experience with the Swiss SONAR score. Literature research was performed to collect data on current evidence. The results were discussed among specialists of the Swiss university centres and private practice, following a structured procedure. Musculoskelatal US was found to be very helpful in establishing the diagnosis and monitoring the evolution of RA, and to be a reliable tool if used by experienced examiners. It influences treatment decisions such as continuing, intensifying or stepping down therapy. The definite modalities of integrating US into the diagnosis and monitoring of RA treatments will be defined within a few years. There are, however, strong arguments to use US findings as of today in daily clinical care. Some practical recommendations about the use of US in RA, focusing on the diagnosis and the use of the SONAR score, are proposed.

Incidence and risk factors for early adjacent vertebral fractures after balloon kyphoplasty for osteoporotic fractures: analysis of the SWISSspine registry

PURPOSE The SWISSspine registry (SSR) was launched in 2005 to assess the safety and effectiveness of balloon kyphoplasty (BKP). In the meantime, repeated reports on high rates of adjacent vertebral fractures (ASF) after BKP of vertebral insufficiency fractures were published. The causes for ASF and their risk factors are still under debate. The purpose of this study was to report the incidence and potential risk factors of ASF within the SSR dataset. METHODS The SSR data points are collected perioperatively and during follow-ups, with surgeon- and patient-based information. All patients documented with a monosegmental osteoporotic vertebral insufficiency fracture between March 2005 and May 2012 were included in the study. The incidence of ASF, significant associations with co-variates (patient age, gender, fracture location, cement volume, preoperative segmental kyphosis, extent of kyphosis correction, and individual co-morbidities) and influence on quality of life (EQ-5D) and back pain (VAS) were analyzed. RESULTS A total of 375 patients with a mean follow-up of 3.6 months was included. ASF were found in 9.9 % (n = 37) and occurred on average 2.8 months postoperatively. Preoperative segmental kyphosis >30° (p = 0.026), and rheumatoid arthritis (p = 0.038) and cardiovascular disease (p = 0.047) were significantly associated with ASF. Furthermore, patients with ASF had significantly higher back pain at the final follow-up (p = 0.001). No further significant associations between the studied co-variates and ASF were seen in the adjusted analysis. CONCLUSIONS The findings suggest that patients with a preoperative segmental kyphosis >30° or patients with co-morbidities like rheumatoid arthritis and a cardiovascular disease are at high risk of ASF within 6 months after the index surgery. In case of an ASF event, back pain levels are significantly increased. LEVEL OF EVIDENCE IV.

Impact of anti-inflammatory treatment on the onset of uveitis in juvenile idiopathic arthritis: Longitudinal analysis from a nation-wide paediatric rheumatological database

PURPOSE Based on a nation-wide database, this study analysed the influence of methotrexate (MTX), TNF inhibitors and a combination of the two on uveitis occurrence in JIA patients. METHODS Data from the National Paediatric Rheumatological Database in Germany were used in this study. Between 2002 and 2013, data from JIA patients were annually documented at the participating paediatric rheumatological sites. Patients with JIA disease duration of less than 12 months at initial documentation and ≥2 years of follow-up were included in this study. The impact of anti-inflammatory treatment on the occurrence of uveitis was evaluated by discrete-time survival analysis. RESULTS A total of 3,512 JIA patients (mean age 8.3±4.8 years, female 65.7%, ANA-positive 53.2%, mean age at arthritis onset 7.8±4.8 years) fulfilled the inclusion criteria. Mean total follow-up time was 3.6±2.4 years. Uveitis developed in a total of 180 patients (5.1%) within one year after arthritis onset. Uveitis onset after the first year was observed in another 251 patients (7.1%). DMARD treatment in the year before uveitis onset significantly reduced the risk for uveitis: MTX (HR 0.63, p=0.022), TNF inhibitors (HR 0.56, p<0.001) and a combination of the two (HR 0.10, p<0.001). Patients treated with MTX within the first year of JIA had an even a lower uveitis risk (HR 0.29, p<0.001). CONCLUSION The use of DMARDs in JIA patients significantly reduced the risk for uveitis onset. Early MTX use within the first year of disease and the combination of MTX with a TNF inhibitor had the highest protective effect. This article is protected by copyright. All rights reserved.

Early-life exposure to endotoxin alters hypothalamic–pituitary–adrenal function and predisposition to inflammation

We have investigated whether exposure to Gram-negative bacterial endotoxin in early neonatal life can alter neuroendocrine and immune regulation in adult animals. Exposure of neonatal rats to a low dose of endotoxin resulted in long-term changes in hypothalamic–pituitary–adrenal (HPA) axis activity, with elevated mean plasma corticosterone concentrations that resulted from increased corticosterone pulse frequency and pulse amplitude. In addition to this marked effect on the development of the HPA axis, neonatal endotoxin exposure had long-lasting effects on immune regulation, including increased sensitivity of lymphocytes to stress-induced suppression of proliferation and a remarkable protection from adjuvant-induced arthritis. These findings demonstrate a potent and long-term effect of neonatal exposure to inflammatory stimuli that can program major changes in the development of both neuroendocrine and immunological regulatory mechanisms.

Sleep Patterns and Parents’ Experience in Caring for Young Children Newly Diagnosed with Juvenile Idiopathic Arthritis

Thesis (Ph.D.)--University of Washington, 2016-05

HFE genotyping demonstrates a significant incidence of hemochromatosis in up differentiated arthritis

Objective Hereditary hemochromatosis is a common autosomal recessive disorder of iron metabolism. Among Northern Europeans the carrier frequency is estimated to be I in 10, while up to 1 in 200 is affected by the disease. Arthropathy is one early clinical manifestation of this disease, but the articular features are often misdiagnosed. In this study the two frequent mutations of the HLA-linked hemochromatosis gene (HFE) were investigated, in a rheumatology clinic population. Methods Two hundred and six consecutive patients (mean age 57.7 years; 38 male/168 female) attending a rheumatology clinic over a period of 14 months were screened for HFE mutations (C282Y and H63D). All standard diagnostic procedures were used to identify the aetiology: of the arthropathy. Mutations were evaluated by separation on PAGE of digested PCR amplificates of DNA (by SnapI and Bcl-I, for C282Y and H63D, respectively) obtained from PBMCs. Results The C282Y and H63D allele frequencies were 4.5 and 12.8 inpatients with rheumatic diseases. Five patients were homozygote for H63D (2.4%), and one,for C282Y (0.5%). Five patients were compound heterozygous (2.4%). The observed C282Y allele frequency in rheumatic patients with undifferentiated arthritis was 12.9 and exceeded that of healthy subjects (p = 0.01). Conclusions Determination of the HFE genotype is clinically useful in patients with arthritis of unknown origin, to allow early diagnosis of hemochromatosis.

Psoriatic arthritis: epidemiology, clinical features, course, and outcome

Psoriatic arthritis (PsA) has been defined as a unique inflammatory arthritis associated with psoriasis. Its exact prevalence is unknown, but estimates vary from 0.3% to 1% of the population. The clinical features described initially are recognised by most experienced clinicians, although they are most distinct in early disease. Initially, PsA typically presents as an oligoarticular and mild disease. However, with time PsA becomes polyarticular, and it is a severe disease in at least 20% of patients. Patients with PsA who present with polyarticular disease are at risk for disease progression. In addition to progression of clinical and radiological damage, health related quality of life is reduced among patients with PsA. It important to note that patients included in recent drug trials resemble patients followed prospectively in a clinic.

Macrophages and CD4 T-cells in rheumatoid arthritis and their modulation by JAK inhibitors

Background: Rheumatoid arthritis (RA) is a chronic inflammatory arthritis that causes significant morbidity and mortality and has no cure. Although early treatment strategies and biologic therapies such as TNFα blocking antibodies have revolutionised treatment, there still remains considerable unmet need. JAK kinase inhibitors, which target multiple inflammatory cytokines, have shown efficacy in treating RA although their exact mechanism of action remains to be determined. Stratified medicine promises to deliver the right drug to the right patient at the right time by using predictive ‘omic biomarkers discovered using bioinformatic and “Big Data” techniques. Therefore, knowledge across the realms of clinical rheumatology, applied immunology, bioinformatics and data science is required to realise this goal. Aim: To use bioinformatic tools to analyse the transcriptome of CD14 macrophages derived from patients with inflammatory arthritis and define a JAK/STAT signature. Thereafter to investigate the role of JAK inhibition on inflammatory cytokine production in a macrophage cell contact activation assay. Finally, to investigate JAK inhibition, following RA synovial fluid stimulation of monocytes. Methods and Results: Using bioinformatic software such as limma from the Bioconductor repository, I determined that there was a JAK/STAT signature in synovial CD14 macrophages from patients with RA and this differed from psoriatic arthritis samples. JAK inhibition using a JAK1/3 inhibitor tofacitinib reduced TNFα production when macrophages were cell contact activated by cytokine stimulated CD4 T-cells. Other pro-inflammatory cytokines such as IL-6 and chemokines such as IP-10 were also reduced. RA synovial fluid failed to stimulate monocytes to phosphorylate STAT1, 3 or 6 but CD4 T-cells activated STAT3 with this stimulus. RNA sequencing of synovial fluid stimulated CD4 T-cells showed an upregulation of SOCS3, BCL6 and SBNO2, a gene associated with RA but with unknown function and tofacitinib reversed this. Conclusion: These studies demonstrate that tofacitinib is effective at reducing inflammatory mediator production in a macrophage cell contact assay and also affects soluble factor mediated stimulation of CD4 T-cells. This suggests that the effectiveness of JAK inhibition is due to inhibition of multiple cytokine pathways such as IL-6, IL-15 and interferon. RNA sequencing is a useful tool to identify non-coding RNA transcripts that are associated with synovial fluid stimulation and JAK inhibition but these require further validation. SBNO2, a gene that is associated with RA, may be biomarker of tofacitinib treatment but requires further investigation and validation in wider disease cohorts.

Early growth response genes 2 and 3 regulate the expression of Bcl6 and differentiation of T follicular helper cells

T follicular helper (Tfh) cells support differentiation of B cells to plasma cells and high affinity antibody production in germinal centers (GC) and Tfh differentiation requires the function of B cell lymphoma 6 (Bcl6). We have now discovered that early growth response gene (Egr) 2 and 3 directly regulate the expression of Bcl6 in Tfh cells which is required for their function in regulation of GC formation. In the absence of Egr2 and 3, the expression of Bcl6 in Tfh cells is defective leading to impaired differentiation of Tfh cells resulting in a failure to form GCs following virus infection and defects in production of anti-viral antibodies. Enforced expression of Bcl6 in Egr2/3 deficient CD4 T cells partially restored Tfh differentiation and GC formation in response to virus infection. Our findings demonstrate a novel function of Egr2/3 which is important for Tfh cell development and Tfh cell mediated B cell immune responses.

Lady Nugent and Tom Cringle on the veranda : early nineteenth century observations on a Caribbean architectural feature

This study of the veranda as seen through the eyes of Lady Maria Nugent and Michael Scott, alias Tom Cringle, clearly demonstrates the important role that the piazza, as it was then more commonly known, played in the life of early nineteenth century Caribbean colonial society. The popularity of the veranda throughout the region, in places influenced by different European as well as African cultures, and among all classes of people, suggests that the appeal of this typical feature was based on something more than architectural fashion. A place of relative comfort in hot weather, the veranda is also a space at the interface of indoors and outdoors which allows for a wide variety of uses, for solitary or small or large group activities, many of which were noted by Nugent and Scott. Quintessentially, the veranda is a place in which to relax and take pleasure, not least of which is the enjoyment of the prospect, be it a panoramic view, a peaceful garden or a lively street scene. Despite the great changes in the nature of society, in the Caribbean and in many other parts of the world, the veranda and related structures such as the balcony continue to play at least as important a role in daily life as they did two centuries ago. The veranda of today’s Californian or Australian bungalow, and the balcony of the apartment block in the residential area of the modern city are among the contemporary equivalents of the lower and upper piazzas of Lady Nugent’s and Tom Cringle’s day.