Perspectives on epigenetic-based immune intervention for rheumatic diseases

Rheumatic disease can loosely be described as any painful condition affecting the loco-motor system, including joints, muscles, connective tissues, and soft tissues around the joints and bones. There is a wide spectrum of rheumatic diseases, many of which involve autoimmunity, including systemic lupus erythematosus and rheumatoid arthritis. A significant body of evidence now links aberrant epigenetic regulation of gene expression with rheumatic disease and points toward the use of epigenetic targeting agents as potential new treatment options, particularly for those conditions associated with an autoimmune element. In this perspective, I will briefly cover the current knowledge surrounding this area in the field of rheumatology.     

The role of stress in rheumatic diseases

Rheumatology patients frequently note the occurrence of stressful or traumatic life events prior to the onset of their illness and/or a relationship between stress and disease flares. For our patients, identifying causal events could represent an effort to give meaning to a chronic and often disabling disease, while noting a link between stress and flares may proffer a sense of control. Whatever purpose the report of stress as an etiological or maintaining factor may serve, the science exploring a causal relationship between stress and autoimmune disease onset and course is expanding. Moreover, stress can also induce symptoms such as pain via nonimmunological mechanisms.     

Current treatment of hepatitis C-associated rheumatic diseases

The hepatitis C virus (HCV) is both hepatotropic and lymphotropic, responsible for a great number of hepatic and extrahepatic immune-system disorders that comprise the so-called HCV syndrome. HCV-associated rheumatic diseases are characterized by frequent clinico-serological overlap; therefore, correct classification of individual patients is necessary before therapeutic decisions are made. This is particularly difficult to do, however, because of the coexistence of viral infection and complex autoimmune alterations. In this context, mixed cryoglobulinemia syndrome (MCs) represents the prototype of virus-related autoimmune-lymphoproliferative diseases. MCs can be treated at different levels by means of etiological treatment with antivirals (peg-interferon-alpha plus ribavirin) aimed at HCV eradication and/or pathogenetic/symptomatic treatments directed to both immune-system alterations and the vasculitic process (rituximab, cyclophosphamide, steroids, plasmapheresis, and so on). In clinical practice, the therapeutic strategy should be modulated according to severity/activity of the MCs and possibly tailored to each individual patient''s conditions. Cryoglobulinemic skin ulcers may represent a therapeutic challenge, which should be managed by means of both local and systemic treatments. HCV-associated arthritis should be differentiated from the simple comorbidity of HCV infection and classical rheumatoid arthritis. It may be treated with low doses of steroids and/or hydroxychloroquine; the use of biologics (rituximab) may be considered in more severe cases. Primary Sjögren''s syndrome is rarely associated with HCV infection, while sicca syndrome and myalgia are frequently detectable in hepatitis C patients, with or without cryoglobulinemic vasculitis. Other autoimmune rheumatic disorders (poly/dermatomyositis, polyarteritis nodosa, osteosclerosis, fibromyalgia, and so on) have been reported as potentially associated with HCV infection in patient populations from different countries, suggesting the role of genetic and/or environmental co-factors. The therapeutic approach to these disorders should be decided according to each individual patient''s evaluation, including hepatic, virological, and immunological findings.     

SAPHO syndrome: Is a range of pathogen-associated rheumatic diseases extended?

SAPHO syndrome, representing a constellation of synovitis, acne, palmo-plantar pustulosis, hyperostosis, and osteitis, is now recognized as a distinct medical entity: a reactive infectious osteitis. Genetic, immunological, and bacterial mechanisms are implicated in the development of the disease. Diagnostic problems may arise due to non-complete manifestations of SAPHO: either acne and arthritis or acne and anterior wall osteitis with an unclear pustulosis history. The interventional study of Assmann et al. is a significant addition to a long range of publications showing an association of SAPHO with Propionibacterium acnes. Randomized control studies are needed to confirm the effects of antibiotic therapy.     

Clinical relevance of autoantibodies in systemic rheumatic diseases

Autoantibodies directed to intracellular antigens are serological hallmarks of systemic rheumatic diseases. Identification of circulating autoantibodies is helpful in establishing the correct diagnosis, indicating the prognosis and providing a guide to treatment and follow-up. Some autoantibodies are included in diagnostic and classification criteria for diseases such as anti-Sm antigen and anti-double-stranded DNA antibodies in systemic lupus erythematosus, anti-U1 nuclear ribonucleoprotein antibodies in mixed connective tissue disease, and anti-SS-A/Ro and anti-SS-B/La antibodies in Sjögren's syndrome. Over the past 30 years, the identification of new autoantibody systems was advanced by the initiation or adaptation of novel techniques such as double immunodiffusion to detect antibodies to saline-soluble nuclear antigens, extraction-reconstitution and ELISA techniques to detect histone and chromatin antibodies, immunoblotting and immunoprecipitation to detect a wide range of antibodies directed against naturally occurring and recombinant proteins. These techniques have been made possible by advances in cellular and molecular biology and in turn, the sera from index patients have been important reagents to identify novel intracellular macromolecules. This paper will focus on the clinical relevance of several autoantibody systems described by Tan and his colleagues over the past 30 years.Abbreviations ANA antinuclear antibody - CENPs centromere proteins - CTD connective tissue disease - DIA drug-induced autoimmunity - DIL drug-induced lupus - HIV human immunodeficiency virus - IIF indirect immunofluorescence - JCA juvenile chronic arthritis - MCTD mixed connective tissue disease - MSA mitotic spindle apparatus - NOR nucleolar organizer - NuMA nuclear mitosis antigen - PBC primary biliary cirrhosis - PCNA proliferating cell nuclear antigen - PM polymyositis - RA rheumatoid arthritis - RNP ribonucleoprotein - SLE systemic lupus erythematosus - SS Sjögren's syndrome - SSc systemic sclerosis - UCTD undifferentiated connective tissue disease     

Side effects of antibiotics in rheumatic diseases]

Complications due to antibiotic therapy in rheumatic patients subjected to season bicillin prophylaxis in Minsk within 1965--1975 and in patients with extensive collagenoses were studied. Allergic complications mainly ih the form of allergic reactions in the patients treated with bicillin-3 or picillin-5 were observed in 7.8--16.8 per cent of the patients. Within 10 years 52 cases of anaphylactic shock due to the bicillin use were recorded. Side reactions to antibiotics were observed in 16 (17.3 per cent) out of 92 patients with extensive collagenoses. For prophylaxis of the above complications it is recommended to use rational antibiotic therapy in rheumatic patients, strict registration of allergological states in the anamnesis, testing of microbial sensitivity to the antibiotics.     

Ultrasound scatter-spacing based diagnosis of focal diseases of the liver

Ultrasound returns from liver shows periodicity arising from periodic scattering centers within tissue. Focal diseases such as tumors interrupt this structure. In this paper, we propose the use of a wavelet transform based technique to estimate the inter-scatterer-distribution (ISS) in diagnosing focal diaseases of the liver. The efficacy of the method is illustrated with simulated and clinical ultrasound images. The mean value (MSS) of the ISS has been proposed as a signature for focal diseases, but its effectiveness has not been established yet. We show that the ISS distribution may function as a feature to characterize focal diseases even when its mean value MSS fails. The method proposed in this paper works even when data is non-stationary.     

Experimental stress in inflammatory rheumatic diseases: a review of psychophysiological stress responses

Introduction  

Stressful events are thought to contribute to the aetiology, maintenance and exacerbation of rheumatic diseases. Given the growing interest in acute stress responses and disease, this review investigates the impact of real-life experimental psychosocial, cognitive, exercise and sensory stressors on autonomic, neuroendocrine and immune function in patients with inflammatory rheumatic diseases.     

Role of infection in the pathogenesis of rheumatic diseases

Advanced immunological technology has revealed immunological abnormalities not only in some chronic and autoimmune connective tissue disorders but also in conditions like infective arthritis where infection apparently seems to play the only role. On the other hand role of infection in the pathogenesis of some connective tissue disorders has recently gained much importance from the observation of clinical, pathological and immunological similarities between these diseases and certain infectious diseases occurring in animal models. Meanwhile, knowledge gained into human leucocyte-A system and its association with certain diseases opens another angle in etiopathogenesis of certain rheumatic diseases. It has been postulated that adaptive mechanism of a microbe or the binding between the human leucocyte-A molecule and carbohydrate moiety of a microbe may set up an autoimmune reaction and in the presence of some triggering factors in the environment may lead on to disease manifestations. An attempt has been made to discuss the role of infection in the outcome of rheumatic diseases such as septic arthritis, polyarteritis nodosa, rheumatic fever, enteropathic arthritis, ankylosing spondylitis, rheumatoid arthritis and systemic lupus erythematoses in genetically susceptible individuals producing immunological abnormalities.