1,721,077 research outputs found
Can the events of early life influence the development of rheumatoid arthritis?
No full textI am often asked the same question by newly diagnosed patients, “Why me? Why did I get rheumatoid arthritis?” The easy response is to trot out an answer that both genes and environmental factors are important. However, it is difficult to provide detail to the sequence of events, and the relative importance of each, needed to induce the chronic inflammation of rheumatoid arthritis (RA).Genetic factors are clearly important. HLA-DRB1 alleles have repeatedly been shown to be associated with the development of RA. Genome-wide studies have also identified other genes both within and outside the major histocompatibility complex (MHC)1. In contrast, advances in our understanding of the role of the environment have often been slower and received less attention. Nevertheless, progress has been made. This is particularly true for exposure to tobacco smoke that has been shown in many studies to be a strong risk factor for the development of RA2. Smoking exposure is also a key example of the importance of interactions between genes and environment.Despite some success there are major challenges to studying the role of environmental factors in the etiology of RA. One of these is the fact that disease commonly starts in middle age. This allows the opportunity for many different exposures throughout life to have had an effect on disease development over many decades. It has become clear that immunological and inflammatory changes begin many years before the onset of joint pain and swelling. The autoantibodies rheumatoid factor (RF) and anti-cyclic citrullinated peptides (anti-CCP) and a raised C-reactive protein (CRP) are all detectable in serum years before symptoms begin3. This has led to the idea that a major block to unraveling the role of environmental factors in RA may be that we are “looking too late”4. Perhaps crucial environmental exposures are missed when we don’t look early enough. If this is true then is it biologically plausible that events during neonatal life and childhood could have lifelong effects?There is now a large body of evidence suggesting that early life events can lead to disease in later life. Work in this area, initially in relation to cardiovascular disease, led to the hypothesis of the “fetal origins of adult disease” proposed by David Barker5. The hypothesis proposes that early life development in adverse circumstances produces a “thrifty phenotype” that prepares the offspring for a more challenging environment. This in turn produces unintended adverse consequences later in life. An example of this is seen in the increased likelihood of hypertension in adults who had low birth weight6. Some of these effects may be mediated through a re-setting of hypothalamic-pituitary-adrenal (HPA) and growth hormone/insulin-like growth factor-1 (GH/IGF-1) axes. For example, low birth weight appears to result in the programming of the HPA axis to produce more cortisol7,8.Early life events may effect the development of autoimmune disease in 2 main ways. The first is through the effects of poor fetal and infant growth as described for low birth weight and hypertension and the second through early life exposure to exogenous factors including microorganisms. Early life growth has been shown to have effects on the development of autoimmune thyroid disease, with low birth weight being associated with increased thyroid autoimmunity9,10. In contrast, development of type I diabetes has been associated with higher weight at 6 months of age11.In this issue of The Journal Simard and colleagues have shown a lack of association between preterm birth or being breastfed and incident RA in women12. The study was carried out using a large number of individuals from the Nurses’ Health Study (NHS) and the Nurses’ Health Study II (NHSII). The same group has shown an association between high birth weight and a greater risk of developing adult RA in the NHS. Interestingly, they have also shown that higher birth weight was associated with an increased incidence of developing systemic lupus erythematosus in the same cohort13. Other groups have shown associations between high birth weight and development of RA14, and low birth weight being protective for the development of RA and juvenile idiopathic arthritis (JIA) (a nonsignificant trend)15. However, birth weight and infant growth have been shown to have no effect on the development of RF in adults16. In general, high birth weight seems to increase the likelihood of RA in later life. The new finding that preterm birth does not affect the likelihood of developing RA does not detract from this.The new results on breastfeeding are in contrast to previous findings that initiation of early breast feeding is associated with the development of RA14 and that HLA-DR4-negative individuals who are RF-positive are more likely to have been breastfed17. There are differences in the populations studied, and diverse results from different groups may also show the difficulty in studying these effects in RA. However, the most recent study contains the largest number of individuals and has the most detailed information on the degree of exposure to breastfeeding.One major difficulty with defining associations between environmental factors and a complex disease like RA is its heterogeneity. This may ultimately be addressed by exact phenotyping of patients into different disease subgroups. This subtyping is likely to increase the reliability of future studies including those looking at environmental factors. The importance of this approach has already been highlighted by studies showing that the effect of breastfeeding in the development of RF is dependent on the presence or absence of HLA-DR417.So does all this work help to answer the patient’s question as to why they developed RA? Well, maybe. It suggests that large babies are more likely to develop RA, that being preterm has no effect, and that if breastfeeding is important it is probably less so. Perhaps high birth weight results in the programming of the HPA axis to produce less cortisol and shifts the balance towards chronic inflammation
Intravenous pulses of methylprednisolone for systemic lupus erythematosus
No full textBackground: Intravenous (IV) pulses of methylprednisolone (MEP) commonly are used to treat severe manifestations of systemic lupus erythematosus (SLE). However, despite wide use of this treatment the best dose, timing, and the situations in which this treatment should be used remain largely anecdotal. Aim: To review the mechanisms of action and evidence for clinical use of IV MEP in the treatment of SLE.Method: The literature on MEP use in SLE from 1966 to 2002, using PubMed from the National Library of Medicine, was reviewed. Results: As with other modes of corticosteroid administration, IV MEP has significant anti-inflammatory and immunosuppressive actions. These actions have been shown to be effective in treating SLE in clinical trials, for lupus nephritis. The studies are mainly uncontrolled and retrospective. Long-term observations from a few double-blind prospective trials suggest that monthly pulses of MEP, in addition to IV cyclophosphamide, may be useful. Pulse MEP is beneficial for several serious manifestations of SLE, such as neuro-psychiatric lupus, pulmonary hemorrhage, severe blood dyscrasias, cardiomyopathy, and vasculitis. However, significant side effects may occur, mostly infections, which are worse in patients with hypoalbuminemia. Conclusion: IV pulses of MEP rapidly immunosuppress patients with organ and/or life-threatening manifestations of SLE. However, the gold standard 1 g/day for 3 consecutive days is associated with significant infectious complications and lower doses may be just as useful
Inflammation and dementia: Using rheumatoid arthritis as a model to develop treatments?
No full textDementia is a major international public health problem which looks set to grow as the ageing population increases. Despite large amounts of investment there has been relatively little progress in developing new therapies to combat this. There is a growing body of evidence that both local and systemic inflammation are important in dementia; with cerebral inflammation occurring secondarily to beta-amyloid plaques, raised levels of serum inflammatory molecules and cytokines being present in Alzheimer's disease patients and systemic inflammation being associated with cerebral microvasculature disease in vascular dementia. Observational studies had suggested that non-steroidal anti-inflammatory drugs may reduce the risk of dementia, but subsequent interventional studies have been disappointing. More recently some observational studies have suggested a protective effect from conventional synthetic disease modifying anti-rheumatic drugs (csDMARDS) and tumour necrosis factor inhibiting (TNFi) biological therapies. Treatments for inflammatory rheumatic diseases have previously been repurposed and used successfully in other diseases, such as TNFi for inflammatory bowel disease. There are also studies looking at the use of csDMARDs such as methotrexate to improve outcomes after cardiovascular events. Ongoing interventional trials are currently looking at whether therapies designed to treat inflammatory and autoimmune diseases have the potential to be used to treat dementia.</p
Anti-TNF-induced lupus
No full textThe use of protein-based anti-TNF-alpha therapies such as antibodies and soluble TNF-alpha receptors is commonly associated with the induction of autoantibodies, whereas anti-TNF-induced lupus (ATIL) is rare. ATIL can occur with any of the available TNF inhibitors, but the frequency and clinical characteristics of ATIL vary between different drugs. Cutaneous, renal and cerebral involvement as well as dsDNA antibodies are more common in ATIL compared to classical drug-induced lupus (DIL), suggesting different pathogenic mechanisms of ATIL and DIL. True ATIL must be clinically differentiated from mixed CTD, SLE or overlap syndromes unmasked, but not induced, by anti-TNF-alpha treatment of unclassified polyarthritis. The pathogenesis of ATIL is still unknown. Concomitant immunosuppression can reduce autoantibody formation in ATIL, and withdrawal of anti-TNF-alpha therapy usually leads to resolution of symptoms. Steroids and/or immunosuppressive therapy may be required in severe cases
Statins as modulators of bone formation
No full textThe use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) to reduce serum cholesterol is well described. However, the recent finding that statins have direct effects on bone was unexpected. A number of epidemiological studies have recently been published that explore the effects of statins on bone mineral density and risk of fracture in humans. Statins may act by directly stimulating the expression of bone morphogenetic protein-2 and increasing osteoblast differentiation or, like nitrogen-containing bisphosphonates, may have effects on the mevalonate pathway that leads to inhibition of osteoclast activity and osteoblast apoptosis. In addition, the demonstration that statins can inhibit inflammation and encourage angiogenesis offers other possibilities for action
Bone morphogenetic proteins in the development and healing of synovial joints
No full textObjectives:
To review current knowledge of the role of bone morphogenetic proteins (BMPs) in joint formation and how this may be relevant to healing in adult joints.Method:
Review of published literature using a search of the PubMed database (1966 to 2000) made available by the National Library of Medicine. Additional articles of historical interest were identified from the bibliographies of published literature.Results:
BMPs and a related family, the growth and differentiation factors (GDFs), are stimulators of bone and cartilage formation in the developing skeleton. They, together with their antagonists, play key roles in the specification of the joint site and cavitation of synovial joints during embryonic development. Disruption of the GDF-5 gene in mice and humans is associated with abnormal joint formation. In situ hybridization studies have shown that BMPs are expressed during formation of synovial joints in the embryo. However, excessive BMP activity leads to obliteration of joints because of cartilage overgrowth. BMPs are being considered as therapeutic agents to stimulate healing of articular cartilage after damage. Evidence suggests that BMPs are present in adult joints and have roles in healing and maintenance. However, inflammatory cytokines and growth factors present in damaged joints modulate the actions of BMPs. Conclusions:
BMPs, and in particular GDF-5, are involved in synovial joint formation. They may also have effects on the maintenance and healing of adult joints, but factors present after damage may alter their effectiveness.Relevance:
Articular cartilage heals poorly after damage. BMPs may be useful therapeutically to stimulate healing of damaged articular cartilage. Increased knowledge of their role in joint formation will improve understanding of how to use them
ERAP1 in the pathogenesis of ankylosing spondylitis
No full textThe endoplasmic reticulum aminopeptidase 1 (ERAP1) performs a major role in antigen processing, trimming N-terminally extended peptides to the final epitope for presentation by major histocompatibility complex class I molecules. Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) within ERAP1 as being associated with disease, in particular ankylosing spondylitis (AS). AS is a polygenic chronic inflammatory disease with a strong genetic link to HLA-B27 known for over 40 years. The association of ERAP1 SNPs with AS susceptibility is only observed in HLA-B27-positive individuals, which intersect on the antigen processing pathway. Recent evidence examining the trimming activity of polymorphic ERAP1 highlights its role in generating peptides for loading onto and stabilizing HLA-B27, and the consequent alterations in the interaction of specific NK cell receptors, and the activation of the unfolded protein response as important in the mechanism of disease pathogenesis. Here, we discuss the recent genetic association findings linking ERAP1 SNPs with AS disease susceptibility and the effect of these variants on ERAP1 function, highlighting mechanisms by which AS may arise. The identification of these functional variants of ERAP1 may lead to better stratification of AS patients by providing a diagnostic tool and a potential therapeutic target
Lupus, vaccinations and COVID-19: what we know now
No full textSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus causing Coronavirus disease 2019 (COVID-19), has had a huge impact on health services, with a high mortality associated with complications including pneumonia and acute respiratory distress syndrome. Patients with systemic lupus erythematosus (SLE) are at increased risk of viral infections, and recent data suggests they may be at an increased risk of poor outcomes with COVID-19. This may be particularly true for those on rituximab or high dose steroids. A huge international effort from the scientific community has so far resulted in the temporary authorisation of three vaccines which offer protection against SARS-CoV-2, with over 30 other vaccines being evaluated in ongoing trials. Although there has historically been concern that vaccines may trigger disease flares of SLE, there is little convincing evidence to show this. In general lupus patients appear to gain good protection from vaccination, although there may be reduced efficacy in those with high disease activity or those on immunosuppressive therapies, such as rituximab or high dose steroids. Recent concerns have been raised regarding rare clotting events with the AstraZeneca/Oxford vaccine and it is currently unknown whether this risk is higher for those patients with secondary antiphospholipid syndrome. With the possibility of annual COVID vaccination programmes in the future, prospective data collection and registries looking at the effect of vaccination on SLE disease control, the incidence of COVID-19 in SLE patients and severity of COVID-19 disease course would all be useful. As mass vaccination programmes begin to roll out across the world, we assess the evidence of the use of vaccines in SLE patients and in particular vaccines targeting SARS-CoV-2.</p
Phase I studies: the role of publicly funded academic-healthcare partnerships
Full text linkEmanuel and colleagues’ meta-analysis found that phase I studies are very safe.1 However, the accompanying editorial mentioned that phase I studies are a “secret realm” and that “most studies are conducted outside academic medical centres at private facilities run by pharmaceutical companies or contract research organisations.”2After a major safety problem at a commercial phase I facility in 2006,3 the UK Medicines and Healthcare products Regulatory Agency (MHRA) introduced an accreditation scheme to enhance phase I safety standards in the UK. There are now four publicly funded phase I accredited clinical research facilities in the UK that have been open to non-commercial facilities since 2013. These include one university-hospital partnership (the Southampton National Institute for Health Research (NIHR) Wellcome Trust Clinical Research Facility) funded by the National Institute for Health Research. This provides an environment for early phase studies within the heart of an acute NHS hospital along with academic input from local university investigators. Phase I studies in patient populations and healthy volunteers are a crucial part of drug development. The UK Department of Health NIHR experimental medicine infrastructure has created a setting that delivers industry and publicly funded phase I trials while allowing recruitment from the entire UK population.<br/
Functionally distinct ERAP1 haplotype combinations distinguish individuals with ankylosing spondylitis
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