Rheumatoid arthritis and pregnancy: evolution of disease activity and pathophysiological considerations for drug use

It has long been known that pregnancy and childbirth have a profound effect on the disease activity of rheumatic diseases. For clinicians, the management of patients with RA wishing to become pregnant involves the challenge of keeping disease activity under control and adequately adapting drug therapy during pregnancy and post-partum. This article aims to summarize the current evidence on the evolution of RA disease activity during and after pregnancy and the use of anti-rheumatic drugs around this period. Of recent interest is the potential use of anti-TNF compounds in the preconception period and during pregnancy. Accumulating experience with anti-TNF therapy in other immune-mediated inflammatory diseases, such as Crohn's disease, provides useful insights for the use of TNF blockade in pregnant women with RA, or RA patients wishing to become pregnant.     

Mineralocorticoid receptors: evolutionary and pathophysiological considerations

Mineralocorticoid receptors (MR), glucocorticoid receptors (GR), progesterone receptors (PR), and androgen receptors (AR) comprise a closely related subfamily within the human 49-member nuclear receptor family. These receptors and their cognate ligands play major roles in homeostasis, reproduction, growth, and development, despite which their evolution and diversification remains incompletely understood. Several conflicting models have been advanced for the evolution of this subfamily. We have thus undertaken Bayesian and maximum likelihood phylogenetic analyses of this subfamily. The Bayesian consensus and maximum likelihood trees support a basal position for MR, with the PR and AR forming a sister clade. We next performed analyses using topological constraints to directly contrast the likelihood of seven phylogenetic models. In these analyses, three models have similar support: one proposes two sister clades (MR and GR, PR and AR); the other two propose a different subfamily member (MR or GR) to be the first to have diverged. Ancestral state reconstructions at sites critical for physiological function show that the S810L mutation in the MR, which results in the MR being similar to estrogen receptors and the more distantly related retinoic acid receptor-α is likely to reflect the ancestral receptor sequence before the divergence of this subfamily and provides further support for MR having been the first of the subfamily to diverge. Finally, we drew on pathophysiological comparisons to help to distinguish the different models. On the basis of our phylogenetic analyses and pathophysiological considerations, we propose that the MR was the first to diverge from the ancestral gene lineage from which this subfamily derived.     

Neuropathic pain in osteoarthritis: A review of pathophysiological mechanisms and implications for treatment

Objectives

Osteoarthritis (OA) is the leading cause of musculoskeletal pain and functional disability worldwide, affecting a growing number of individuals in the western society. Despite various conservative and interventional treatment approaches, the overall management of the condition is problematic, and pain—the major clinical problem of the disease—remains sub-optimally controlled. The objectives of this review are to present the pathophysiologic mechanisms underlying the complexity of pain in OA and to discuss the challenges for new treatment strategies aiming to translate experimental findings into daily clinical practice.

Methods

A narrative literature review of studies investigating the existence of a neuropathic component in OA pain was conducted. We searched PubMed, Embase and Scopus for English language publications. A hand-search of reference lists of relevant studies was also performed.

Results

Recent advances have shed additional light on the pathophysiology of osteoarthritic pain, highlighting the contribution of central pain pathways together with the sensitisation of peripheral joint receptors and changes of the nociceptive process induced by local joint inflammation and structural bone tissue changes. Thus, a neuropathic pain component may be predominant in individuals with minor joint changes but with high levels of pain refractory to analgesic treatment, providing an alternative explanation for osteoarthritic pain perception.

Conclusion

A growing amount of evidence suggests that the pain in OA has a neuropathic component in some patients. The deeper understanding of multiple mechanisms of OA pain has led to the use of centrally acting medicines that may have a benefit on alleviating osteoarthritic pain. The ineffective pain management and the increasing rates of disability associated with OA mandate for change in our treatment paradigm.     

Signalling, inflammation and arthritis: NF-kappaB and its relevance to arthritis and inflammation

In the synovial cells of patients with RA, activation of thenuclear factor-B (NF-B) pathway results in the transactivationof a multitude of responsive genes that contribute to the inflammatoryphenotype, including TNF- from macrophages, matrix metalloproteinasesfrom synovial fibroblasts and chemokines that recruit immunecells to the inflamed pannus. This is largely a consequenceof activation of the ‘canonical’ NF-B pathway thatinvolves heterodimers of p50/p65. Whilst much information onthe role of NF-B in inflammation has been gleaned from geneticdeficiency of the respective genes in mice, important differencesexist in the signalling networks between human and murine immunecells and immortalized cell lines. Despite these differencesat the molecular level, the importance of NF-B in inflammationis undisputed and inhibition of the pathway is widely believedto have great potential as a therapeutic target in RA. Commercialeffort has gone into developing inhibitors of NF-B activation.However, inhibition of the NF-B activation can result in anexacerbation of inflammation if TNF- production by macrophagesis not controlled. It will be important that such inhibitorsare carefully monitored before their long-term use in chronicinflammatory conditions such as RA. KEY WORDS: NF-B, Signalling pathways, Review Submitted 13 July 2007; revised version accepted 4 October 2007.     

COVID-19 and ethnicity: A novel pathophysiological role for inflammation

IntroductionThere have been recent mounting concerns regarding multiple reports stating a significantly elevated relative-risk of COVID-19 mortality amongst the Black and Minority Ethnic (BAME) population. An urgent national enquiry investigating the possible reasons for this phenomenon has been issued in the UK. Inflammation is at the forefront of COVID-19 research as disease severity appears to correlate with pro-inflammatory cytokine dysregulation. This narrative review aims to shed light on the novel, pathophysiological role of inflammation in contributing towards the increased COVID-19 mortality risk amongst the BAME population.MethodsSearches in PubMed, Medline, Scopus, medRxiv and Google Scholar were performed to identify articles published in English from inception to 18^th June 2020. These databases were searched using keywords including: ‘COVID-19’ or ‘Black and Minority Ethnic’ or ‘Inflammation’. A narrative review was synthesized using these included articles.ResultsWe suggest a novel pathophysiological mechanism by which acute inflammation from COVID-19 may augment existing chronic inflammation, in order to potentiate a ‘cytokine storm’ and thus the more severe disease phenotype observed in the BAME population. Obesity, insulin resistance, cardiovascular disease, psychological stress, chronic infections and genetic predispositions are all relevant factors which may be contributing to elevated chronic systemic inflammation amongst the BAME population.ConclusionOverall, this review provides early insights and directions for ongoing research regarding the pathophysiological mechanisms that may explain the severe COVID-19 disease phenotype observed amongst the BAME population. We suggest ‘personalization’ of chronic disease management, which can be used with other interventions, in order to tackle this.     

Oxygen radicals and hypertension

The Author reviews the problem, starting with a short introduction about oxygen free radicals. He discusses the vascular factor, emphasizing the importance of several known relaxants, EDRF, prostacyclin, monooxigenated arachidonate derivatives, ANF, hydrogen peroxide and hydroxyl radical. He analyses the involvement of free radicals in kidney damage and presents evidence for their formation during cerebral vascular accidents.     

The coagulation system in children: developmental and pathophysiological considerations

The coagulation system in children is complex and ever changing, a fact encapsulated in the term developmental hemostasis. Studies confirm that there are quantitative and almost certainly qualitative differences in the coagulation system with age, and the control of these changes comes from something external to the liver. What remains uncertain is the magnitude of the qualitative changes and the implications of the changes for the growing child. At the very least, developmental hemostasis probably provides a protective mechanism for neonates and children and hence contributes to the decreased risk of thromboembolic and/or hemorrhagic events in these age groups. In addition, developmental hemostasis could also reflect the role that hemostatic proteins play in physiological development and hence the demand of other processes, such as angiogenesis. Finally, without doubt, developmental hemostasis affects the interactions of anticoagulant drugs with the coagulation system. This article will initially discuss the most recent evidence with respect to qualitative age-related changes in the coagulation system. Subsequently the article will discuss the coagulation system during childhood in light of the three aforementioned areas of clinical impact and suggest possible strategies to further understand this complex and exciting field of study.     

Gastro-oesophageal reflux disease in obesity: pathophysiological and therapeutic considerations

Gastro‐oesophageal reflux disease (GERD) is common in obese patients. Apart from the physical discomfort and the economic burden, GERD may increase morbidity and mortality through its association with oesophageal carcinoma. The pathophysiology of GERD differs between obese and lean subjects. First, obese subjects are more sensitive to the presence of acid in the oesophagus. Second, hiatal hernia, capable of promoting GERD by several mechanisms, is more prevalent among the obese. Third, obese subjects have increased intra‐abdominal pressure that displaces the lower oesophageal sphincter and increases the gastro‐oesophageal gradient. Finally, vagal abnormalities associated with obesity may cause a higher output of bile and pancreatic enzymes, which makes the refluxate more toxic to the oesophageal mucosa. The altered body composition associated with obesity affects the pharmacokinetics of drugs. There are no data regarding the efficacy of any of the drugs used for GERD treatment. The dosages of cimetidine and ranitidine should be calculated according to the patient’s ideal body weight, not their actual weight. Of the operative procedures used for weight loss, Roux‐en‐Y gastric bypass was found to be most effective for GERD, while gastric banding was associated with a high prevalence of reflux. This review outlines the pathophysiology and the treatment of GERD in obesity with emphasis on the therapeutic considerations in this population of patients.     

Vascular calcification in rheumatoid arthritis: Prevalence, pathophysiological aspects and potential targets

Individuals with rheumatoid arthritis (RA) are at increased risk for morbidity and mortality from cardiovascular disease. Excess cardiovascular mortality in RA patients cannot be fully explained by conventional cardiovascular risk factors. The purpose of this review is to discuss recent progress concerning the prevalence and pathophysiological aspects of vascular calcification in RA. RA patients have early-onset diffuse calcification involving multiple vascular beds compared to age and sex-matched controls. Pathogenesis of vascular calcification in RA patients is not fully understood, but specific mediators such as proinflammatory cytokines and not global inflammation could be involved. The possible link between osteoporosis and vascular calcification in RA will not be discussed. Finally, potential targets to reduce vascular calcification in RA will be discussed.     

Oxygen radicals and human disease

Toxic oxygen free radicals have been implicated as important pathologic mediators in many clinical disorders. We discuss the chemistry of oxygen radical production and the roles of iron and of various antioxidants as well as the diseases that have received active attention in oxy-radical research. Particular attention is focused on cigarette smoke oxidants, ischemia-reperfusion-induced radical production, carcinogenesis, and aging. Such research may well provide a firm foundation for therapeutic breakthroughs.     

Metalloproteinases, inflammation, and rheumatoid arthritis

Ideally, the inflammatory response occurs rapidly to terminate infection. It also must halt in a timely manner to stop this reaction from inflicting self damage. Such a highly regulated process results from altering balances in pro- and anti-inflammatory signals orchestrated by multiple cell types and factors within the tissue microenvironment. The discovery of new substrates of metalloproteinases within this microenvironment has disclosed a new function in inflammation. The role of these proteases now extends beyond extracellular matrix remodelling enzymes to that of mediators of inflammatory signals involving various chemokines and cytokines. As natural inhibitors of these metalloproteinases, TIMPs have the potential of regulating the inflammatory response and affecting diseases such as rheumatoid arthritis. TIMP-3, in particular, stands out as an important regulator of inflammation with its ability to specifically inhibit proinflammatory cytokines and tissue destruction in the joint.