Treating chronic non-cancer pain in older people – More questions than answers?

There is little evidence specifically relating to drug treatments for pain in older people, but much can be extrapolated from what we already know. The evidence about drug treatments for chronic non-cancer pain is changing, driven by major improvements in understanding of clinical trial analysis and by the adoption of patient-centered outcomes of proven economic benefit. There is clear evidence of lack of useful effect, or insufficient evidence of effect for a number of commonly used drugs, including paracetamol, topical rubefacients, low concentration topical capsaicin, and for strong opioids in chronic non-cancer pain. In musculoskeletal pain there is evidence of efficacy for NSAIDs, tramadol, and tapentadol, and in neuropathic pain for duloxetine, pregabalin, and gabapentin, with weak evidence for amitriptyline. The new perspective is of drugs that work well in a minority of patients, but hardly at all in the remainder. The goal of treatment is large reductions in pain, by 50% or more. This outcome, and only this outcome, is associated with large benefits in terms of improved sleep, reduced depression, and large gains in function and quality of life. It is not possible to predict which patient will benefit from which drug, but early success or failure appears to be predictive of long-term success or failure. The emphasis is on stopping treatments that do not work and switching to other drugs in the same or different class, so that any potential future risk of treatment is balanced by very large and immediate benefit.     

Chronic granulomatous disease: more than the lack of superoxide?

Chronic granulomatous disease (CGD) is an inherited disease characterized by severe and recurrent bacterial and fungal infections manifested in most cases in early childhood. Phagocytic cells of CGD patients are unable to produce superoxide anions, and their efficiency in bacterial killing is significantly impaired. Recent work has shown alterations in the electrophysiological properties of CGD granulocytes, which might contribute to the pathogenesis of the disease. The new aspects that we discuss in this review concern the proton channel function of gp91phox (the electron-transporting subunit of the NADPH oxidase) and the electrogenic activity of the active enzyme complex, which can affect the transmembrane trafficking of several ions. Based on the reviewed data, we also propose a hypothesis that the absence of a functional NADPH oxidase in CGD neutrophils could result in altered ion compositions within intracellular and intraphagosomal spaces during the process of phagocytosis.     

Psychosis: an autoimmune disease?

Psychotic disorders are common and disabling. Overlaps in clinical course in addition to epidemiological and genetic associations raise the possibility that autoimmune mechanisms may underlie some psychoses, potentially offering novel therapeutic approaches. Several immune loci including the major histocompatibility complex and B‐cell markers CD19 and CD20 achieve genome‐wide significance in schizophrenia. Emerging evidence suggests a potential role via neurodevelopment in addition to classical immune pathways. Additionally, lymphocyte biology is increasingly investigated. Some reports note raised peripheral CD19⁺ and reduced CD3⁺ lymphocyte counts, with altered CD4 : CD8 ratios in acute psychosis. Also, post‐mortem studies have found CD3⁺ and CD20⁺ lymphocyte infiltration in brain regions that are of functional relevance to psychosis. More specifically, the recent paradigm of neuronal surface antibody‐mediated (NSAb) central nervous system disease provides an antigen‐specific model linking adaptive autoimmunity to psychopathology. NSAbs bind extracellular epitopes of signalling molecules that are classically implicated in psychosis such as NMDA and GABA receptors. This interaction may cause circuit dysfunction leading to psychosis among other neurological features in patients with autoimmune encephalitis. The detection of these cases is crucial as autoimmune encephalitis is ameliorated by commonly available immunotherapies. Meanwhile, the prevalence and relevance of these antibodies in people with isolated psychotic disorders is an area of emerging scientific and clinical interest. Collaborative efforts to achieve larger sample sizes, comparison of assay platforms, and placebo‐controlled randomized clinical trials are now needed to establish an autoimmune contribution to psychosis.     

Retroviruses in autoimmune liver disease: genetic or environmental agents?

Retroviruses have been implicated in the pathogenesis of several human autoimmune conditions including Sj?gren's syndrome, primary biliary cirrhosis, immune mediated diabetes, and multiple sclerosis. The human intracisternal A type particle derived from Sj?gren's syndrome patients' salivary glands was the first retrovirus to be isolated from a human autoimmune disorder but the agent has yet to be cloned. In primary biliary cirrhosis patients, virus like particles have been observed by electron microscopy in biliary epithelium, endogenous retroviral sequences have been cloned from liver samples, and antibody reactivity to the human intracisternal A type particle has been observed in the majority of patients tested. However, there is no evidence to link the endogenous retroviral sequences in primary biliary cirrhosis patients to the retroviral antibody reactivity or virus like particles. In other patients with liver disease, reactivity to the human intracisternal A type particle was observed in a small but significant proportion of patients with hepatitis C virus infection. If the intracisternal A type particle is an endogenous retrovirus, it is interesting to speculate that hepatitis C virus infection may modulate the endogenous retroviral expression, as chronic hepatitis C has been linked with the development of Sj?gren's syndrome. Furthermore, many patients with chronic hepatitis C virus infection have reactivity to an autoantigen of unknown significance known as GOR that has protein sequence homology with both hepatitis C virus nucleocapsid protein as well as HTLV-1 gag. This may be an another example of an endogenous retroviral protein acting as an autoantigen in liver disease patients. At this time, there is little evidence to suggest that endogenous retroviruses are infectious agents that cause autoimmune disease but they may be implicated as either genetic elements or antigens. Further studies will be required to characterize the role that both exogenous and endogenous retroviruses play in the pathogenesis of autoimmune liver diseases.     

Caspases: more than just killers?

Proteases of the caspase family constitute the central executioners of apoptosis. Several recent observations suggest that caspases and apoptosis-regulatory molecules exert important functions beyond that of cell death, including the control of T-cell proliferation and cell-cycle progression. Here, Los and colleagues propose a model that directly connects cell suicide mechanisms to the regulation of cell-cycle progression.     

When is an autoimmune disease not an autoimmune disease?

What are the enviromental triggers and genetic susceptibilities underlying the development of autoimmune diseases? These and other questions were addressed at a recent meeting in Finland¹.     

Nitric oxide in autoimmune disease: cytotoxic or regulatory mediator?

Nitric oxide (NO) is released locally during inflammatory autoimmune diseases and is believed to contribute to tissue destruction. However, recent studies are not fully consistent with such a simple role for NO. Here, Hubert Kolb and Victoria Kolb-Bachofen discuss data that suggest a role for NO in autoimmune diseases as an important regulator of the T helper 1 (Th1)/Th2 balance.     

Idiopathic bilateral vestibulopathy: an autoimmune disease?

Bilateral vestibulopathy (BV) is the loss of function of both peripheral labyrinths or of the eighth nerves. Its etiology remains obscure in approximately 20% to 50% of cases (so-called idiopathic bilateral vestibulopathy, IBV). Alternatively, the cause could be viral or vascular; to date, causative gene mutations have not been identified.     

A quantitative model of autoimmune disease and T-cell vaccination: does more mean less?

According to a simple mathematical model, the activated effector T cells that cause an autoimmune disorder can also cure the disease if administered in large doses. This prediction has been tested in the nonobese diabetic (NOD) mouse model and demonstrates that administration of intermediate doses of a diabetogenic T-cell clone caused early hyperglycemia, whereas a higher dose cured the disease. As discussed here by Lee Segel and colleagues, the proposed application of T-cell vaccination to treat clinical disease obliges immunologists to consider the quantitative complexities of regulation.     

Could oxytocin reduce autoimmune disease in COVID-19?

Disruption of immune and neuroendocrine system function has been shown to play a key role in COVID-19. Oxytocin is vitally important for the immune and neuroendocrine systems. However, oxytocin dysfunction might occur in COVID-19 leading to autoimmune disease. Intranasal oxytocin may be effective in turning off an overactive immune system. This could be a powerful approach to avoid possible autoimmune diseases after COVID-19.     

Coronary artery bypass grafting for Fabry's disease: veins more suitable than arteries?

Coronary artery bypass grafting was performed in a 54-year-old man affected by untreated Fabry's disease. Left internal mammary artery (LIMA) and saphenous vein grafts were implanted. Surgical samples of LIMA revealed diffuse glycosphyngolipid infiltration of smooth muscle cells, whereas SV was normal. After surgery, the patient received antithrombotic and enzyme replacement therapy. At 1-year follow-up, LIMA graft occluded, whereas saphenous vein graft remained patent. In Fabry's disease, veins, probably because of a low pressure load, seem to be spared from glycosphingolipid accumulation and are more suitable than arteries for grafting. A preventive histology of conduits is suggested before graft selection.     

Spatial attention: more than intrinsic alerting?

It has been proposed that the right hemisphere alerting network co-activates, either directly or via the brainstem, the attention system in the parietal cortex involved in spatial attention. The observation that impaired alertness and sustained attention can predict the outcome of neglect might suggest such a relationship, too. In the present fMRI study, we intended to analyse and compare the functional anatomy of two attentional conditions both involving intrinsic (endogenous) alerting and fixation but differing with respect to the degree of spatially distributed attention by using the same paradigm under two different attentional conditions. In a group of ten participants, both a focused and a distributed visuospatial attention condition evoked similar patterns of activation in dorsolateral prefrontal regions, in the anterior cingulate gyrus, in the superior and inferior parietal cortex as well as in the superior temporal gyrus and in the thalamus. These activation foci were stronger in the right hemisphere under both conditions. After subtraction of the alertness condition with focused spatial attention, distributed spatial attention with stimuli appearing at unpredictable locations within both visual fields induced additional bilateral activations only in the left and right superior parietal cortex and in the right precuneus suggesting that these regions are specific for a more widespread dispersion of spatial attention.     

Central tolerance: Essential for preventing autoimmune disease?

Recessive central tolerance of developing T cells is caused by antigen‐induced deletion of immature cortical double positive and medullary single positive thymocytes in the absence of TCR editing. There are few examples where it can be convincingly shown that recessive tolerance plays an essential role in preventing autoimmune disease. This is in part due to the fact that genetic factors predisposing to autoimmune disease could conceivably contribute to both recessive tolerances in the thymus and antigen‐induced generation of Treg. Of considerable interest is the notion that several epitopes recognized by disease‐causing T‐cell clones exhibit poor class II MHC binding consistent with the notion that the limited availability of such epitopes in the thymus could lead to failing recessive tolerance, while more abundant quantities in peripheral lymphoid tissues could result in activation of T cells that have escaped central tolerance.     

Inflammatory bowel disease: autoimmune or immune-mediated pathogenesis?

The pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), is still unclear, but both autoimmune and immune-mediated phenomena are involved. Autoimmune phenomena include the presence of serum and mucosal autoantibodies against intestinal epithelial cells in either form of IBD, and against human tropomyosin fraction five selectively in UC. In addition, perinuclear antineutrophil cytoplasmic antibodies (pANCA) are common in UC, whereas antibodies against Saccharomyces cerevisiae (ASCA) are frequently found in CD. Immune-mediate phenomena include a variety of abnormalities of humoral and cell-mediated immunity, and a generalized enhanced reactivity against intestinal bacterial antigens in both CD and UC. It is currently believed that loss of tolerance against the indigenous enteric flora is the central event in IBD pathogenesis. Various complementary factors probably contribute to the loss of tolerance to commensal bacteria in IBD. They include defects in regulatory T-cell function, excessive stimulation of mucosal dendritic cells, infections or variants of proteins critically involved in bacterial antigen recognition, such as the products of CD-associated NOD2/CARD15 mutations.     

Sudden sensorineural hearing loss: an autoimmune disease?

Objectives

To review our current knowledge of the pathogenesis of sudden sensorineural hearing loss, including viral infection, vascular occlusion and immune system-mediated mechanisms, and to discuss the pathogenesis as it relates to pharmacotherapy.

Systematic review methodology

Relevant publications on the pathogenesis of sudden sensorineural hearing loss from 1944 to 2010 were analysed.

Results and conclusions

Sudden sensorineural hearing loss is defined as hearing loss of 30 dB in three sequential frequencies over 3 days or less. It can be an isolated symptom or the presenting symptom of a systemic disease. The aetiology and pathogenesis remain unknown. Detailed investigation typically reveals a specific cause in about 10% of patients. Proposed theories of causation include viral infections, vascular occlusion and immune system-mediated mechanisms. A variety of therapies have been proposed based on the various proposed aetiologies.     

Anti-GBM glomerulonephritis: a T cell-mediated autoimmune disease?

Anti-glomerular basement membrane (GBM) glomerulonephritis, which was among the earliest recognized human autoimmune diseases, is characterized by the presence of anti-GBM antibody. It has been a prototypical example of autoantibody-mediated autoimmune disease. However, decades of research on this disease, based either on clinical observations or experimental models, have revealed that T cell-mediated cellular immunity may potentially be a more important mediator of glomerulonephritis. We have made several breakthroughs in understanding the T cell-mediated mechanism causing this disease in a rat model based on Goodpasture's antigen, non-collagen domain 1 of alpha3 chain of type IV collagen (Col4alpha3NC1). We demonstrated that anti-GBM glomerulonephritis was induced by either passive transfer of Col4 alpha3NC1-specific T cells or active immunization with the nephritogenic T cell epitope of Col4alpha3NC1. Immunization with the T cell epitope also triggered production of anti-GBM antibodies to diversified GBM antigens. Thus, a single nephritogenic T cell epitope alone is sufficient to induce the clinical spectrum of anti-GBM glomerulonephritis, including proteinuria, glomerular injury, and anti-GBM antibody. A possible T cell-mediated mechanism for causing human anti-GBM disease is proposed.