Risk of severe COVID-19 in patients with inflammatory rheumatic diseases treated with immunosuppressive therapy in Scotland.

OBJECTIVE: To investigate the association of severe coronavirus disease 2019 (COVID-19) in patients with inflammatory rheumatic diseases (IRDs) treated with immunosuppressive drugs. METHOD: A list of 4633 patients on targeted - biological or targeted synthetic - DMARDs in March 2020 was linked to a case-control study that includes all cases of COVID-19 in Scotland. RESULTS: By 22 November 2021, 433 of the 4633 patients treated with targeted DMARDS had been diagnosed with COVID-19, of whom 58 had been hospitalized. With all those in the population not on DMARDs as the reference category, the rate ratio for hospitalized COVID-19 associated with DMARD treatment was 2.14 [95% confidence interval (CI) 2.02-2.26] in those on conventional synthetic (cs) DMARDs, 2.01 (95% CI 1.38-2.91) in those on tumour necrosis factor (TNF) inhibitors as the only targeted agent, and 3.83 (95% CI 2.65-5.56) in those on other targeted DMARDs. Among those on csDMARDs, rate ratios for hospitalized COVID-19 were lowest at 1.66 (95% CI 1.51-1.82) in those on methotrexate and highest at 5.4 (95% CI 4.4-6.7) in those on glucocorticoids at an average dose > 10 mg/day prednisolone equivalent. CONCLUSION: The risk of hospitalized COVID-19 is elevated in IRD patients treated with immunosuppressive drugs compared with the general population. Of these drugs, methotrexate, hydroxychloroquine, and TNF inhibitors carry the lowest risk. The highest risk is associated with prednisolone. A larger study is needed to estimate reliably the risks associated with each class of targeted DMARD.

The Effect of Anti-rheumatic Drugs on the Skeleton.

The therapeutic armamentarium for rheumatoid arthritis has increased substantially over the last 20 years. Historically antirheumatic treatment was started late in the disease course and frequently included prolonged high-dose glucocorticoid treatment which was associated with accelerated generalised bone loss and increased vertebral and non-vertebral fracture risk. Newer biologic and targeted synthetic treatments and a combination of conventional synthetic DMARDs prevent accelerated systemic bone loss and may even allow repair of cortical bone erosions. Emerging data also gives new insight on the impact of long-term conventional synthetic DMARDs on bone health and fracture risk and highlights the need for ongoing studies for better understanding of "established therapeutics". An interesting new antirheumatic treatment effect is the potential of erosion repair with the use of biologic DMARDs and janus kinase inhibitors. Although several newer anti-rheumatic drugs seem to have favorable effects on bone mineral density in RA patients, these effects are modest and do not seem to influence the fracture risk thus far. We summarize recent developments and findings of the impact of anti-rheumatic treatments on localized and systemic bone integrity and health.

Diagnosis and Management of Osteoporosis During COVID-19: Systematic Review and Practical Guidance.

It is acknowledged that the COVID-19 pandemic has caused profound disruption to the delivery of healthcare services globally. This has affected the management of many long-term conditions including osteoporosis as resources are diverted to cover urgent care. Osteoporosis is a public health concern worldwide and treatment is required for the prevention of further bone loss, deterioration of skeletal micro-architecture, and fragility fractures. This review provides information on how the COVID-19 pandemic has impacted the diagnosis and management of osteoporosis. We also provide clinical recommendations on the adaptation of care pathways based on experience from five referral centres to ensure that patients with osteoporosis are still treated and to reduce the risk of fractures both for the individual patient and on a societal basis. We address the use of the FRAX tool for risk stratification and initiation of osteoporosis treatment and discuss the potential adaptations to treatment pathways in view of limitations on the availability of DXA. We focus on the issues surrounding initiation and maintenance of treatment for patients on parenteral therapies such as zoledronate, denosumab, teriparatide, and romosozumab during the pandemic. The design of these innovative care pathways for the management of patients with osteoporosis may also provide a platform for future improvement to osteoporosis services when routine clinical care resumes.

The relationship between obesity and fractures.

There has been very limited analysis of the relationship between obesity and fractures in the orthopaedic literature. It has been established for some years that underweight individuals are at greater risk of proximal femoral fractures but recently there has been interest in the susceptibility of obese post-menopausal females to fracture. We have undertaken an analysis of 4886 adult patients who presented with a fracture and had their BMI assessed. Analysis has confirmed the relationship between underweight individuals and proximal femoral fractures but there is also a negative association between obesity and clavicle fractures in males and females and with calcaneal fractures in females. There is a positive relationship between obesity and proximal humeral, finger phalangeal and ankle fractures in males and with humeral diaphyseal, carpal and ankle fractures in females. There was no relationship found between open or multiple fractures and obesity.

Cognitive function, disease burden and the structural connectome in systemic lupus erythematosus.

Objective To investigate brain structural connectivity in relation to cognitive abilities and systemic damage in systemic lupus erythematosus (SLE). Methods Structural and diffusion MRI data were acquired from 47 patients with SLE. Brains were segmented into 85 cortical and subcortical regions and combined with whole brain tractography to generate structural connectomes using graph theory. Global cognitive abilities were assessed using a composite variable g, derived from the first principal component of three common clinical screening tests of neurological function. SLE damage ( LD) was measured using a composite of a validated SLE damage score and disease duration. Relationships between network connectivity metrics, cognitive ability and systemic damage were investigated. Hub nodes were identified. Multiple linear regression, adjusting for covariates, was employed to model the outcomes g and LD as a function of network metrics. Results The network measures of density (standardised ß = 0.266, p = 0.025) and strength (standardised ß = 0.317, p = 0.022) were independently related to cognitive abilities. Strength (standardised ß = -0.330, p = 0.048), mean shortest path length (standardised ß = 0.401, p = 0.020), global efficiency (standardised ß = -0.355, p = 0.041) and clustering coefficient (standardised ß = -0.378, p = 0.030) were independently related to systemic damage. Network metrics were not related to current disease activity. Conclusion Better cognitive abilities and more SLE damage are related to brain topological network properties in this sample of SLE patients, even those without neuropsychiatric involvement and after correcting for important covariates. These data show that connectomics might be useful for understanding and monitoring cognitive function and white matter damage in SLE.

Fatigue and cognitive function in systemic lupus erythematosus: associations with white matter microstructural damage. A diffusion tensor MRI study and meta-analysis.

Objective The objective of this study was to investigate fatigue and cognitive impairments in systemic lupus erythematous (SLE) in relation to diffuse white matter microstructural brain damage. Methods Diffusion tensor MRI, used to generate biomarkers of brain white matter microstructural integrity, was obtained in patients with SLE and age-matched controls. Fatigue and cognitive function were assessed and related to SLE activity, clinical data and plasma biomarkers of inflammation and endothelial dysfunction. Results Fifty-one patients with SLE (mean age 48.8 ± 14.3 years) were included. Mean diffusivity (MD) was significantly higher in all white matter fibre tracts in SLE patients versus age-matched healthy controls ( p < 0.0001). Fatigue in SLE was higher than a normal reference range ( p < 0.0001) and associated with lower MD ( ß = -0.61, p = 0.02), depression ( ß = 0.17, p = 0.001), anxiety ( ß = 0.13, p = 0.006) and higher body mass index ( ß = 0.10, p = 0.004) in adjusted analyses. Poorer cognitive function was associated with longer SLE disease duration ( p = 0.003) and higher MD ( p = 0.03) and, in adjusted analysis, higher levels of IL-6 ( ß = -0.15, p = 0.02) but not with MD. Meta-analysis (10 studies, n = 261, including the present study) confirmed that patients with SLE have higher MD than controls. Conclusion Patients with SLE have more microstructural brain white matter damage for age than the general population, but this does not explain increased fatigue or lower cognition in SLE. The association between raised IL-6 and worse current cognitive function in SLE should be explored in larger datasets.

High mortality in younger patients with major osteoporotic fractures.

Data were gathered with regard to mortality after fractures in 1006 younger patients. Results revealed that major osteoporotic fractures of the hip and humerus and drinking alcohol to excess were related to an increased risk of mortality. INTRODUCTION: Major osteoporotic fractures are known to be associated with increased mortality in older individuals. It is less clear whether this also applies to younger patients. METHODS: Date were gathered regarding patient demographics, fracture pattern, mechanism of injury, as well as smoking and alcohol intake at the time of injury in consecutive patients aged between 40 and 55 who presented to a UK trauma centre over a 12-month period. Mortality data was taken from the electronic patient records and was cross referenced with data from the General Registrar Office of Scotland. Cox regression analysis was used to identify independent predictors of mortality after adjusting for confounding factors. RESULTS: The study cohort consisted of 1006 patients, of which 53% were male. The commonest mechanism of injury was a fall. We obtained complete data regarding mortality for all patients at a median of 5.4 years (inter-quartile range 5.1 to 5.6). During this period, 46 patients were identified as being deceased. The overall standardised mortality ratio for the cohort was substantially increased relative to the age and sex matched general population with a ratio of 3.89 (95% confidence intervals (CI) 1.59 to 6.19). Alcohol excess and fractures involving the humerus and the neck of femur were independent predictors of mortality. CONCLUSIONS: Young individuals with hip and humerus fractures have a significantly increased mortality risk after their injury relative to the general population. The results of our study suggest that this may be in part due to a high prevalence of alcohol excess.

A snapshot of biologic drug development: Challenges and opportunities.

Since the approval of insulin as the first recombinant therapeutic protein, the prominence of biologic therapies in drug development has grown significantly. Many modalities beyond traditional biologics are now being developed or explored for various indications with significant unmet medical needs. From early traditional replacement proteins to more recent, highly engineered antibodies, oligonucleotides, fusion proteins, and gene constructs, biologic agents have delivered life-changing therapies, despite often having scientifically and technically challenging development programs. This brief review outlines some of the major biotherapeutic classes and identifies the advantages and challenges with the development of these products.

The type 2 cannabinoid receptor regulates susceptibility to osteoarthritis in mice.

OBJECTIVE: Cannabinoid receptors and their ligands have been implicated in the regulation of various physiological processes but their role in osteoarthritis has not been investigated. The aim of this study was to evaluate the role of the type 2 cannabinoid receptor (Cnr2) in regulating susceptibility to osteoarthritis in mice. METHODS: We analysed the severity of knee osteoarthritis as assessed by the Osteoarthritis Research Society International (OARSI) scoring system in mice with targeted deletion of Cnr2 (Cnr2(-/-)) and wild type (WT) littermates. Studies were conducted in mice subjected to surgical destabilisation of the medial meniscus (DMM) and in those with spontaneous age-related osteoarthritis (OA). RESULTS: Osteoarthritis was more severe following DMM in the medial compartment of the knee in Cnr2(-/-) compared with WT mice (mean ± sem score = 4.9 ± 0.5 vs 3.6 ± 0.3; P = 0.017). Treatment of WT mice with the CB2-selective agonist HU308 following DMM reduced the severity of OA in the whole joint (HU308 = 8.4 ± 0.2 vs vehicle = 10.4 ± 0.6; P = 0.007). Spontaneous age related osteoarthritis was also more severe in the medial compartment of the knee in 12-month old Cnr2(-/-) mice compared with WT (5.6 ± 0.5 vs 3.5 ± 0.3, P = 0.008). Cultured articular chondrocytes from Cnr2(-/-) mice produced less proteoglycans in vitro than wild type chondrocytes. CONCLUSION: These studies demonstrate that the Cnr2 pathway plays a role in the pathophysiology of osteoarthritis in mice and shows that pharmacological activation of CB2 has a protective effect. Further studies of the role of cannabinoid receptors in the pathogenesis of osteoarthritis in man are warranted.

Presentation and management of osteoporosis presenting in association with pregnancy or lactation.

In this review, we summarize our current understanding of the pathophysiology of fragility fractures that occur for the first time during pregnancy and lactation, and provide guidance on appropriate investigations and treatment strategies. Most affected women will have had no prior bone density reading, and so the extent of bone loss that may have occurred during pregnancy or lactation is uncertain. During pregnancy, intestinal calcium absorption doubles in order to meet the fetal demand for calcium, but if maternal intake of calcium is insufficient to meet the combined needs of the mother and baby, the maternal skeleton will undergo resorption during the third trimester. During lactation, several hormonal changes, independent of maternal calcium intake, program a 5-10 % loss of trabecular mineral content in order to provide calcium to milk. After weaning the baby, the maternal skeleton is normally restored to its prior mineral content and strength. This physiological bone resorption during reproduction does not normally cause fractures; instead, women who do fracture are more likely to have additional secondary causes of bone loss and fragility. Transient osteoporosis of the hip may affect one or both femoral heads during pregnancy but it involves localized edema and not skeletal resorption. Case reports have described the use of calcitonin, bisphosphonates, strontium ranelate, teriparatide, vertebroplasty, and kyphoplasty to treat post-partum vertebral fractures. However, the need for such treatments is uncertain given that a progressive increase in bone mass subsequently occurs in most women who present with a fracture during pregnancy or lactation.

Short- and long-term racing performance of Standardbred pacers and trotters after early surgical intervention for tarsal osteochondrosis.

REASONS FOR PERFORMING STUDY: Osteochondrosis (OC) is commonly diagnosed in young Standardbred racehorses but its effect on performance when surgically treated at a young age is still incompletely understood. This is especially true for Standardbred pacers, which are underrepresented in the existing literature. OBJECTIVE: To characterise the short- (2-year-old) and long-term (through 5-year-old) racing performance in Standardbred pacers and trotters after early surgical intervention (<17 months of age) for tarsal OC. STUDY DESIGN: Retrospective clinical study. METHODS: The study population consisted of related, age-matched Standardbred racehorses (n = 278; 151 pacers, 127 trotters) with (n = 133) or without (n = 145) one or more tarsal OC lesions. All OC-affected horses were treated surgically prior to being sold as yearlings. Data obtained from publicly available race records for each horse included starts, wins, finishes in the top 3 (win, place or show), earnings and fastest time. Comparisons between OC-affected and unaffected horses were made for the entire population and within gaits. A smaller related population (n = 94) had these performance measures evaluated for their 2-5-year-old racing seasons. RESULTS: Osteochondrosis status was associated with few performance measures. Trotters were at higher risk for lesions of the medial malleolus but lower risk for lesions of the distal intermediate ridge of the tibia than were pacers. Horses with bilateral OC lesions and lateral trochlear ridge (LTR) lesions started fewer races at 2 years of age than those with unilateral lesions or without LTR lesions. CONCLUSIONS: Osteochondrosis seemed to have minimal effect on racing performance in this cohort, although horses with bilateral and LTR lesions started fewer races at 2 years. There was evidence for different distribution of OC lesions among pacers and trotters, which should be explored further. Standardbreds undergoing early removal of tarsal OC lesions can be expected to perform equivalently to their unaffected counterparts.

Unveiling the mysteries of the genetics of osteoporosis.

INTRODUCTION: Osteoporosis is a common disease characterised by low bone mineral density and an increased risk of fragility fractures. METHODS: We conducted a literature review of relevant studies relating to the genetics of osteoporosis. RESULTS: Family studies have revealed that bone density and fractures have a strong heritable component but environmental factors also play an important role. This makes identification of the causative genetic variants challenging. Linkage analysis has been successful in identifying the genes responsible for rare inherited diseases associated with abnormalities of bone mass but has been of limited value in osteoporosis. In contrast, genome-wide association studies in large cohort studies have identified 56 loci with robust evidence of association with bone density and 14 loci that predispose to fractures. Although the effect size of the implicated variants is small, many of the loci contain genes known to be involved in regulating bone cell activity through the RANK and Wnt signalling pathways, whereas others contain novel genes not previously implicated in bone metabolism. In a few instances, whole genome and exome sequencing have been successfully used to identify rare variants of large effect size that influence susceptibility to osteoporosis. CONCLUSION: A future challenge will be to conduct fine mapping and functional analysis of the loci implicated in osteoporosis in order to identify the causal genetic variants and examine the mechanisms by which they influence bone cell function and bone mass. Ultimately this may lead to the identification of biomarkers for susceptibility to osteoporosis and fractures or new therapeutic targets.

Paget's disease of bone.

Paget's disease of bone is a common disorder characterized by increased but disorganized bone remodelling. Some patients are asymptomatic but others present with bone pain or other complications such as fracture and deformity. Major advances have been made in understanding the pathophysiology of Paget's disease in recent years and highly effective agents are now available with which to suppress the abnormal bone turnover that causes the disease. Here we review recent advances in the epidemiology, pathogenesis, clinical features and management of Paget's disease. We also reflect upon the future challenges that remain to be overcome to explain the unusual distribution of the disease and to favourably alter the natural history and prevent the development of complications.

Cost and resource implications with serum angiogenic factor estimation in the triage of pre-eclampsia.

OBJECTIVES: To analyse the economic and resource implications of using plasma soluble fms-like tyrosine kinase-1 s(Flt1) and placenta growth factor (PlGF) measurements in pre-eclampsia evaluation and management. DESIGN: Retrospective cost analysis of our prospective cohort study. SETTING: Boston, Massachusetts (USA). POPULATION: Women (n = 176) presenting to the hospital at <34 weeks of gestation for evaluation of possible pre-eclampsia during 2009-10. Cases without complete cost or outcome data (n = 9) and re-enrolments (n = 18) were excluded. METHODS: Modelled comparisons between the standard approach (combination of blood pressure, urinary protein excretion, alanine aminotransferase and platelet counts) and a novel approach (ratio of plasma sFlt1 and PlGF) using actual hospital data converted to 2012 US dollars in accordance with the Centers for Medicare and Medicaid Services. MAIN OUTCOME MEASURES: Direct 2-week costs and resource use by groups having true or false positive and negative test results for adverse outcomes according to approach. RESULTS: The improved specificity of the novel approach decreased the proportion of women falsely labelled as test-positive from 42.3% (34.4-50.2%) to 4.0% (0.85-7.15%) and increased the proportion correctly labelled as test-negative from 23.5% (16.7-30.3%) to 61.7% (53.9-69.5%). This could potentially reduce average per-patient costs by $1215. Substantial quantities of resources [47.2% (35.7-58.7%) of antenatal admissions and 72.5% (68.0-77.0%) of tests for fetal wellbeing] were unnecessarily used for women who were truly negative. A proportion of iatrogenic preterm deliveries among women with negative results was potentially avoidable representing further cost and resource savings. CONCLUSIONS: Clinical use of the plasma sFlt1 and PlGF ratio improves risk stratification among women presenting for pre-eclampsia evaluation and has the potential to reduce costs and resource use.

Secular changes in Paget's disease: contrasting changes in the number of new referrals and in disease severity in two neighboring regions of Spain.

SUMMARY: We studied the changes in the number of new referrals with Paget's disease of bone (PDB) and severity of PDB in a high prevalence focus and its neighboring region. Referral of patients changed only in the high prevalence focus. The severity of PDB decreased in both regions. These results could suggest the effects of an environmental influence on disease activity. INTRODUCTION: The prevalence and severity of PDB have decreased in several countries over recent years. We previously reported a high radiological prevalence of PDB in Vitigudino. Here we sought to determine if secular changes in the number of new referrals and severity of PDB had occurred over recent years. METHODS: We studied 280 patients with clinically diagnosed PDB who were evaluated at a regional referral center for metabolic bone disease between 1986 and 2009. Changes in the number of new referrals were calculated by relating these data to the number of subjects at risk as determined by population registers. Trends in disease severity were analyzed with alkaline phosphatase (ALP) activity and disease extent on scan. RESULTS: Referrals from the Vitigudino region increased substantially between 1986 and 2003 but fell markedly between 2004 and 2009, although by this time there had been depopulation of the region due to emigration. No significant changes in the rates of referral occurred in the remainder of Salamanca. ALP activity and disease extent decreased in Salamanca, but only ALP activity decreased in Vitigudino. Referrals rate and severity of PDB in Vitigudino were greater than in the remainder of Salamanca. CONCLUSIONS: Referral of patients with clinically diagnosed PDB has remained stable for most of Salamanca during the past 24 years, but substantial changes have been observed in Vitigudino. In agreement with other reports, the severity of PDB has decreased in both regions consistent with the effects of an environmental influence on disease activity.

An appendix to the 2012 IOF-ECTS guidelines for the management of glucocorticoid-induced osteoporosis.

The use of glucocorticoids in the treatment of medical disorders can lead to rapid bone loss and increased risk of fragility fracture. Updated clinical guidelines are needed that accommodate recent advances in fracture risk assessment and new pharmacological interventions to reduce fracture risk. This document serves as an appendix to the 2012 IOF-ECTS guidelines for the management of glucocorticoid-induced osteoporosis.

Management of glucocorticoid-induced osteoporosis.

This review summarizes the available evidence-based data that form the basis for therapeutic intervention and covers the current status of glucocorticoid-induced osteoporosis (GIOP) management, regulatory requirements, and risk-assessment options. Glucocorticoids are known to cause bone loss and fractures, yet many patients receiving or initiating glucocorticoid therapy are not appropriately evaluated and treated. An European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis workshop was convened to discuss GIOP management and to provide a report by a panel of experts. An expert panel reviewed the available studies that discussed approved therapeutic agents, focusing on randomized and controlled clinical trials reporting on bone mineral density and/or fracture risk of at least 48 weeks' duration. There is no evidence that GIOP and postmenopausal osteoporosis respond differently to treatments. The FRAX algorithm can be adjusted according to glucocorticoid dose. Available antiosteoporotic therapies such as bisphosphonates and teriparatide are efficacious in GIOP management. Several other agents approved for the treatment of postmenopausal osteoporosis may become available for GIOP. It is advised to stop antiosteoporotic treatment after glucocorticoid cessation, unless the patient remains at increased risk of fracture. Calcium and vitamin D supplementation as an osteoporosis-prevention measure is less effective than specific antiosteoporotic treatment. Fracture end-point studies and additional studies investigating specific subpopulations (pediatric, premenopausal, or elderly patients) would strengthen the evidence base and facilitate the development of intervention thresholds and treatment guidelines.

Skeletal effects of vitamin D supplementation in postmenopausal black women.

Black women have lower serum 25-hydroxyvitamin D (25[OH]D) levels and higher parathyroid hormone (PTH) levels than white peers but lower bone turnover, suggesting skeletal resistance to PTH. Our objective was to determine if vitamin D supplementation (1,000 IU/day) would prevent bone loss and whether vitamin D receptor (VDR) polymorphisms modify the response. We performed a 2-year randomized, controlled, double-blind study of 1,000 IU vitamin D(3) vs. placebo in postmenopausal black women with serum 25(OH)D levels <20 ng/mL (n = 103). Measurements of 25(OH)D, PTH, and bone turnover were evaluated at baseline and 3, 6, 12, 18, and 24 months. DNA was extracted from peripheral blood leukocytes, and genotyping was conducted using standard techniques. Spine and hip bone mineral density (BMD) was measured at baseline and every 6 months. Serum 25(OH)D increased 11 ng/mL with vitamin D supplementation (p < 0.001), with no change in the placebo group. Vitamin D supplementation produced a significant decline in PTH at 3 months only, with no differences in bone turnover between placebo and vitamin D at any time point. Two-year changes in BMD were not significantly different between placebo- and vitamin D-treated black women at any skeletal site. Despite similar elevations in 25(OH)D, femoral neck BMD was only responsive to vitamin D supplementation in FF subjects (n = 47), not Ff/ff subjects (n = 31). Vitamin D supplementation does not appear to influence bone loss in black women. However, in the FF polymorphism of the VDR gene group, vitamin D supplementation may retard the higher rate of bone loss.