Current Rheumatology Reviews - Volume 1, Issue 3, 2005

Lipid peroxidation (LPO) is a free radical-related process occurring in biologic systems under enzymatic or nonenzymatic control, e.g. for the generation of lipid-derived aldehydes. There is increasing evidence that these aldehydes are causally involved in the pathogenesis of numerous diseases including diabetes, heart failure, atherosclerosis, and neurodegenerative process. 4-hydroxynonenal (HNE) is the most important aldehyde involved in oxidant injury. Classically, HNE was described for a long time as a marker of extensive oxidative stress in various tissues. Recent studies, however, showed that HNE can modulate cellular metabolism, inflammatory responses, as well as apoptosis via its effects on signaling/transcription regulation and protein modification. Interestingly, these pathological processes are all implicated to various degrees in arthritis, but no study has specifically reported the potential role of these aldehydes in rheumatic diseases. Therefore, this review focuses on the relevance of oxidative stress-induced HNE production to the pathophysiology of arthritis at inflammatory and catabolic levels.

Although the pathogenesis of Behcet's disease (BD) is not fully elucidated, a genetic susceptibility to the disease appears to be affected by a polygenic inheritance, including the major histocompatibility complex (MHC) and non-MHC genes. As is true for the well-known regional differences in the disease expression of BD, a genetic susceptibility to BD appears to be different in various ethnic groups. Although HLA-B51 is a genetic factor with the strongest association in most ethnic populations who reside in countries adjacent to the ancient Silk Road, it is still uncertain whether this HLA molecule is directly involved in the pathogenesis of BD. In addition to HLA-B51, the association of BD with the MICA gene has been reported to be the consequence of linkage disequilibrium with HLA-B51, whereas the TNF-1031C allele among TNF gene polymorphisms has been observed to be another risk factor independent of the presence of HLA-B51 in UK Caucasoid patients with BD. Recently, intensive investigations on non-MHC genes, some of which are noted to be associated with a susceptibility to BD in several ethnic groups, are under way.

Ankylosing spondylitis (AS) is so strongly associated with the genetical marker HLA-B27 that the molecule is supposed to play a central role in the pathogenesis of the disease. If this is true, it has to be explained why there is such a difference in pathogenic consequences between certain subtypes of HLA-B27. The subtypes B*2706 and B*2709 play probably no pathogenic role, this in contrast to other subtypes like B*2704 and B*2705 for which such a role is evident. The difference between pathogenic and non-pathogenic subtypes is small and limited to the amino acid residues 114 and 116 on the antigen presenting groove of the molecule. The non-pathogenic molecule HLA-B*2706 has, in contrast to all HLA-B27 molecules associated with the disease, aspartic acid on position 114. This amino acid residue is situated on the rim between the D and the F pocket. The molecule B*2709 has histidine on position 116 on the bottom of the F pocket, which is unique. These small but significant differences were the subject of studies by Ringrose and Lopez de Castro. Ringrose studied the bacterial antigen presenting capacity of HLA-B*2704, but was not already able to compare it with that of B*2706 [1]. Lopez de Castro and his co-workers compared B*2704 and B*2706. They showed that arginine at position 3 of peptides is better presented by B*2706 than by B*2704, whereas alanine and tyrosine at this position show the opposite [2]. These studies have to proceed and will help to reveal how these small differences can be responsible for the difference between health and disease.

Anemia of chronic disease (ACD), one of the most common syndromes in medicine, is observed in patients with chronic infections, inflammatory and neoplastic disorders. All of the factors involved in the development of ACD can be attributed to effects of cytokines, including shortened red cell survival, blunted erythropoietin response to anemia, impaired erythroid colony formation in response to erythropoietin and abnormal mobilization of reticuloendothelial iron stores. Tumor Necrosis Factor-alpha (TNF! ), which is important for the pathophysiology of ACD, may act directly on bone marrow erythroid precursors. Hepcidin is a liver-made peptide, and its synthesis is greatly stimulated by inflammation. The plasma level of erythropoietin (EPO) in anemic patients suffering from inflammation is often low in relation to the blood hemoglobin concentration. Interleukin 1 and TNF! suppress EPO gene expression. ACD is most effectively treated via approaches directed against the underlying cause. There are also some reports addressing that iron supplementation and iron chelation therapy may be useful. If this is not possible, supportive care is given through red cell transfusions or use of recombinant human EPO. Patients with inflammatory disorders showed remarkable hematologic responses to recombinant EPO, although a significant change in rheumatologic picture was not seen.

Fibromyalgia syndrome is a frequent cause of chronic, widespread pain and affects up to 5% of the general population in industrial nations. Both genetics and the environment have been implicated in the development of fibromyalgia, and current research focuses on evaluating neurobiological, psychological, and behavioral factors that play a part in the disease pathogenesis. As we better understand how these factors interact to cause symptoms in groups of individuals, we can design treatment programs that are more effective in individual patients. For example, classes of drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) and opioids which are quite effective for "peripheral" pain are typically ineffective for the "central" pain seen in fibromyalgia. Instead, tricyclic antidepressants (TCA) and other classes of antidepressants, antiseizure drugs, and a number of other neuroactive compounds seem to be more effective. In addition, non-pharmacological therapies such as aerobic exercise and cognitive behavioral therapy are reasonably effective, and frequently underutilized in clinical practice.

Enthesitis is the inflammatory process marked by the insertion of tendons, ligaments and joint capsules on the bone and it is a cardinal feature (and diagnostic criteria) of spondyloarthropathies (SpA). Although it is usually revealed by clinical examination, recent studies using magnetic resonance imaging (MRI) and ultrasonography (US) have confirmed that enthesitis (as well as synovitis) can often be asymptomatic, both in the axial and peripheral skeleta. Therefore, a systematic US study of peripheral entheses could be useful in the diagnostic process of patients suspected with SpA, and peripheral enthesitis scoring systems have been proposed. Recently, power Doppler US (PDUS) has been proved to be useful for differentiating mechanical and inflammatory enthesitis and for monitoring the efficacy of therapy. This article reviews the main anatomical and histopathological aspects of enthesitis and describes the general US features of enthesis and the basic US features of enthesitis, in its various stages. The usefulness of US and PDUS in the diagnosis and assessment of SpA is discussed on the basis of the available literature and our experience.

Alterations of joint biomechanics are known to play a pivotal role in the pathogenesis of osteoarthritis. Open MRI now allows one to assess important biomechanical parameters of diarthrodial joints in vivo during the entire range of joint motion, encompassing all clinically relevant joint positions, and to analyze in particular the influence of muscle activity and neuromuscular control. The current article reviews data of the authors on quantitative, open, functional MR imaging of in vivo joint biomechanics, with focus on the shoulder and knee and gives an overview of the literature on these topics. Further, the article summarizes technical descriptions of the methods used as well as studies on accuracy and reproducibility of the technique. We present normative data on subacromial space width, glenohumeral translation and scapulothoracic motion patterns in the human shoulder joint of young healthy volunteers, and describe their association with gender and body dimensions. Also, alterations of these parameters are reported in different disease entities of the shoulder. We present ongoing work on the functional changes of cartilage contact areas in healthy and pathologic knee joints and we describe how these biomechanical changes are related to alterations of cartilage morphology. Future perspectives of these methods are mentioned in which a combination of open MRI and qMRI of cartilage morphology should give a more detailed insight into the pathogenesis, progression and treatment of osteoarthritis in different joint pathologies.

Systemic lupus erythematosus (SLE) is characterized by the presence of a wide variety of autoantibodies directed against nuclear, cytoplasmic and cell membrane autoantigens. Several lines of evidence, however, suggest that the variety of autoantibodies in SLE may be more limited than was previously thought; different studies clearly suggest that lupus autoantibodies are able to bind multiple antigens. Cross-reactivity, i.e. the ability to bind multiple antigens with high affinity, is not limited to a single autoantibody specificity, but instead seems to be a general property of lupus autoantibodies, distinguishing them from immunization-induced antibodies. Many studies on cross-reactivity have focused on the autoantibodies present exclusively in SLE, and which are therefore considered to be markers of the disease, such as anti-dsDNA, anti-Sm and anti-ribosomal P protein antibodies. However, cross-reactivity has also been shown to be a feature of SLE autoantibodies that are not strictly disease-specific. The structural basis of cross-reactivity is not always clear. It may be due to the presence of common epitopes on different antigens, or to the specific structure of the antigen binding site that can then accommodate different epitopes. Whether one or more mechanisms of cross-reactivity are involved, the ability of an antibody to bind different antigens directly affects its pathogenic potential.

Paget's bone disease (PDB) is a focal metabolic disorder that affects 2-3% of the population older than 60 years and is characterized by increased and grossly distorted bone remodeling, bone hypertrophy, and abnormal bone structure. The disease affects one or several bone pieces and its aetiology remains unclear. The primary cell abnormality in PDB could involve the osteoclasts that are markedly increased in number and size, can have 100 nuclei per cell, and contain paramyxoviral-like nuclear and cytoplasmatic inclusions. Thirty years ago the observation of these inclusions suggested the involvement of paramyxovirus in the PDB pathogenesis. Nevertheless, the paramyxoviral theory is a very controversial one. On the other hand, familial aggregation studies indicate that 40% of affected subjects show a PDB familial history and recent advances in our understanding of the disease come from genetic studies. PDB is genetically heterogeneous, with seven loci (PBD 1-7) reported at this time. Most likely, an interaction between environmental and genetic factors is required for patients to develop PDB and could explain the geographic distribution of the disease as well as its peculiar variable phenotypic presentation.

Intravenous Immunoglobulin (IVIG) has been used since the 1970's for the treatment of a variety of different rheumatologic and infectious diseases. While the therapeutic efficacy of IVIG has been definitively demonstrated in many different disorders, its mechanism(s) of action have remained poorly explained. This is complicated, in part by the difference in pathophysiology of the many diseases it has been used in the treatment of. Regardless of the types of diseases, understanding why transfusing pooled donor antibodies to unscreened patients fails to elicit a detrimental immunologic response, let alone benefit these patients, needs explanation. This review aims to explain how IVIG works by reviewing the medical literature and the relevant basic immunology involved.

A local injection of the 5-HT3 receptor antagonist tropisetron has a distinct analgesic effect on various local diseases of the locomotor system, such as tendinopathy, periarthropathy, trigger points and inflammatory articular processes. The effect of tropisetron matches that of commonly used local anesthetics like lidocaine, prilocaine and others, lasts much longer. Animal experimental and clinical findings seem to indicate that this prolonged action is most likely due to a concomitant antiinflammatory effect of the 5-HT3 receptor antagonist. It may therefore be assumed that this substance will at least partly be able to replace the administration of anesthetics and corticosteroids in the local treatment of rheumatic processes.