Chronic Inflammatory Rheumatic Disorders Research Articles

The Involuntary Weight Loss of the Elderly: Rheumatic Disorders

I read the detailed article by Loser et al. with great interest. With regard to the topic of involuntary weight loss in elderly people, a necessary addition from the perspective of rheumatology and internal medicine is that – in addition to the disorders discussed in the article – chronic inflammatory rheumatic disorders also often constitute a cause of involuntary weight loss and require investigation and adequate treatment (if diagnosed) in patients with weight loss problems. The main entity is the group of vasculitides of the medium or large blood vessels, especially giant cell arteritis/polymyalgia rheumatica. In the latter, weight loss and age >65 years are among the classification criteria, and with an incidence of about 20/100 000 population >50 years of age and a prevalence of about 200/100 000 population this constitutes an often unrecognized internal medical problem in elderly people, not only in specialist university or acute hospitals for rheumatology.

Searching for Potential Biomarkers that can be Used as Biomarkers for Diagnosing Ankylosing Spondylitis

Ankylosing spondylitis (AS) is a chronic systemic inflammatory rheumatic disorder that primarily affects the axial skeleton. To date there is no satisfactory biomarker for diagnosis or prognosis of AS. This study is focused on detection of potential biomarkers for the diagnosis of AS using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) with the ultimate goal of developing a progression biomarker for AS. Protein profiles of sera of 38 AS patients and 38 healthy controls were obtained using ProteinChip arrays. Different arrays and conditions were compared with find out which condition resulted in the optimal discrimination of both groups. Optimal discrimination was reached using weak cation exchange (CM10) and immobilized metal affinity capture coupled with copper (IMAC-Cu(2+)) arrays. Using a multimarker approach on protein profiles obtained with CM10 arrays resulted in a sensitivity of 66% and a specificity of 74%. Using a multimarker approach on protein profiles obtained with IMAC-Cu(2+) arrays resulted in a sensitivity and specificity of 70%. This is the first study that shows that protein profiling in serum using SELDI-TOF-MS can be used as a diagnostic tool for AS. The biomarkers will be validated to confirm if they can be used as progression biomarkers.

Whole body MR imaging in ankylosing spondylitis: a descriptive pilot study in patients with suspected early and active confirmed ankylosing spondylitis

BackgroundAnkylosing spondylitis is a chronic inflammatory rheumatic disorder which usually begins in early adulthood. The diagnosis is often delayed by many years. MR imaging has become the preferred imaging method for detection of early inflammation of the axial skeleton in ankylosing spondylitis.The goal of this study was to assess the frequency and distribution of abnormalities on whole body MR imaging in patients with suspected early ankylosing spondylitis and with active confirmed ankylosing spondylitis.MethodsTen patients with suspected early ankylosing spondylitis and ten patients with confirmed ankylosing spondylitis were enrolled. On an 18-channel MR system, coronal and sagittal T1 weighted and STIR sequences were acquired covering the entire spine, sacrum, anterior chest wall, shoulder girdle, and pelvis. The total examination time was 30 minutes.ResultsIn both groups inflammatory lesions of the lower thoracic spine were frequent (number of patients with suspected early/confirmed ankylosing spondylitis: 7/9). In confirmed ankylosing spondylitis the upper thoracic spine (3/6) and the lumbar spine (4/8) were more commonly involved. The inferior iliac quadrant of the sacroiliac joints was frequently altered in both groups (8/8). The superior iliac (2/5), inferior sacral (6/10) and superior sacral (3/6) quadrants were more frequently affected in confirmed ankylosing spondylitis. Abnormalities of the manubriosternal joint (2/4), the sternoclavicular joints (1/2) and hip joint effusion (4/3) were also seen.ConclusionIn both suspected early ankylosing spondylitis and confirmed ankylosing spondylitis, whole body MR examinations frequently demonstrate inflammatory lesions outside the sacroiliac joints. These lesions are similarly distributed but occur less frequently in suspected early compared to confirmed ankylosing spondylitis. Due to the small sample size in this pilot study these results need to be confirmed in larger studies with this emerging technique.

Anti‐tumour necrosis factor‐α: the dawn of a new era in the treatment of rheumatoid arthritis

The reports from the Kennedy Institute in London in 1993 and 1994 that monoclonal antibodies to the cytokine tumour necrosis factor-α could significantly suppress symptoms and signs of rheumatoid arthritis (RA) will go down in history as one of the events that has changed the face of rheumatology.1, 2 It has changed not only the lives of patients with RA, ankylosing spondylitis (AS) and other chronic rheumatic diseases, but also the way physicians practise in the management of these conditions. American College of Rheumatology ACR50 and ACR70 responses are now readily achievable and in some patients full remission is being reported. As these drugs are used earlier in the onset of RA there is some data to suggest even higher remission rates. The three most commonly used agents, infliximab, etanercept and adalimumab, are now being joined by others, and the pharmaceutical industry is not only producing more TNF inhibitors, but stimulating research into other cytokine inhibitors. The appropriate dose, what drugs to combine with TNF-α inhibitors and a range of other questions still need to be addressed. In an editorial on the first decade of use of TNF-α inhibitors, Kavanaugh et al.3 raise a number of important issues relating to TNF inhibitors: there is synergy between methotrexate and TNF inhibitors; switching from one agent to another may be effective; and; treatment not only improves signs and symptoms and quality of life, but also slows radiological progression. They also raise important issues in relation to such things as toxicity, what is the best strategy for treating partial responders and pose the question as to whether TNF-α inhibitors should be used as initial therapy in early RA. These compounds are still very expensive and this in itself has raised the profile of rheumatologists within the healthcare system (almost to the level of the oncologist) in terms of their interaction with healthcare funders and hospital administrators. The issue of safety of TNF inhibitors is a particularly important one and very relevant to the Asia-Pacific region. There remain concerns about the association of TNF inhibitor use and infections, particularly tuberculosis (TB),4 and this needs to be considered carefully given that the early trials of these drugs were carried out in countries where the incidence of community tuberculosis is much lower than in any of the countries where these drugs are now being used (for example in the south-east Asia-Pacific region). This has led to the development of a number of guidelines5 that need to be considered when using these drugs in such areas. Interest in this topic has stimulated our Journal to provide this supplement which explores the Asia-Pacific experience in biologic therapies. These data and experiences are most important as we cover over half the world's population and the outcomes, both positive and negative, may be quite different to those seen in clinical trials or clinics carried out in Europe or the Americas. We have been able to call upon many prominent rheumatologists from this region to contribute their experience on the use of TNF inhibitors in the management of RA, various spondyloarthropathies, notably AS, and other chronic inflammatory rheumatic disorders. Important questions related to their use include the following. (i) When are these therapies indicated in APLAR patients? (ii) Are there ethnic differences in patients’ clinical responses? (iii) Can APLAR, where a large number of members are developing countries, afford these high-cost therapies? And can patients be maintained on a lower-dose regimen? (iv) While on cost, how pharmaco-economical are these agents? At which point should these novel biologics be considered? And how do they compare with conventional disease-modifying anti-inflammatory drugs (DMARDs)? (v) Are APLAR patients more susceptible to the various possible side-effects of TNF inhibitor agents, particularly chronic infections such as TB? (vi) If TB is a concern, what is (are) the best way(s) to avoid the development of this potentially serious complication? (vii) How should we educate our patients on the use of TNF inhibitors? (viii) What if these therapies fail? Are there alternatives on the horizon? (ix) Finally, what are the clinical effects of anti-TNF-α agents on other immune-mediated rheumatic conditions? We believe that this special issue will add a new and important perspective to data on TNF inhibitors and allow us to understand their use in our region.

Corticosteroid resistance in rheumatoid arthritis: molecular and cellular perspectives.

Corticosteroids are often used to treat a range of chronic autoimmune inflammatory diseases such as asthma, inflammatory bowel disease and rheumatoid arthritis (RA). RA is the most prevalent autoimmune chronic inflammatory rheumatic disorder with a prevalence of 1% in developed nations. It is more common in women than men, suggesting that perturbations of the hormonal systems may be involved in disease pathophysiology. The aetiology of the disease is unknown, but the physiological mechanisms of inflammation involved in this disease share common pathways with other inflammatory situations [1, 2]. However, the reasons why inflammation persists in RA remain unknown but might relate in part to a dysregulation of the interactions between neuroendocrine and immune systems at the onset of acute inflammation [2–6]. Acute inflammation can be initiated by a number of inflammatory triggers. This results in a programmed sequence of physiological mechanisms which begin with the release of tumour necrosis factor alpha (TNF ), interleukin-1 (IL-1 ) and IL-6 [3]. These cytokines activate a cascade of reciprocal local and systemic responses which result in increased secretion of corticotrophin-releasing hormone (CRH) and arginine vasopressin by the hypothalamus and production of adrenocorticotrophic hormone (ACTH), prolactin and macrophage migration inhibitory factor (MIF) by the pituitary gland and cortisol by the adrenal glands. Cortisol dampens inflammation by down-regulating the release of TNF , IL-1 and IL-6 whilst MIF and prolactin counteract the effects of cortisol resulting in a balanced inflammatory/immune response [3–5]. If acute inflammation is not restrained, it enters a chronic phase, a central feature of many chronic autoimmune inflammatory diseases [6]. Neuroendocrine regulation of immune function is essential for survival during stress or infection and to modulate immune responses in inflammatory disease. Corticosteroids are the main effector endpoint of the neuroendocrine immune response to inflammation. At the molecular level, IL-1 , IL-6 and TNF initiate a number of pro-inflammatory intracellular signalling events which include the activation of the transcriptional activities of activator protein-1 (AP-1) and nuclear factorB (NFB) by a phosphorylation-dependent dissociation and/or degradation of Iby specific kinases (Ikinase 1 and 2) in the case of NF-I[7, 8]. These in turn enhance the production of a whole range of pro-inflammatory cytokines. These transcription factors are targets of action by cortisol and other corticosteroid type drugs [9]. NFis involved in the pathogenesis of inflammation in RA [10]. In addition IL-l and TNF also activate the mitogenactivated protein kinase (MAPK) p38 pathway [11]. MAPK p38 activates the kinases MAPKAPK-2, which in turn targets adenosine/uridine-rich elements (AREs) of pro-inflammatory messenger ribonucleic acids (mRNAs) to bring about their stabilization [9, 12, 13]. IL-l and TNF activate the second wave of cytokine release mechanisms [IL-8, IL-12, IL-15, IL-17, IL-18, interferonand , granulocyte–macrophage colony-stimulating factor (GM-CSF), fibroblast growth factor etc.] that augment the homeostatic signals necessary for the subsequent complex cellular/cytokine cascades of reactions, endothelial activation and enhanced cell adhesion. The body attempts to down-regulate inflammation by increasing corticosteroid production [3]. Synthetic corticosteroid analogues such as prednisolone have been made and are often used to treat chronic autoimmune inflammatory disease such as RA, asthma and inflammatory bowel disease. They can effectively reduce the parameters of inflammation such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) and induce disease remission. However, in clinical practice, a proportion of patients fail to respond adequately to corticosteroid therapy [14–16]. On this basis, patients can be divided into corticosteroid sensitive (SS) and corticosteroid resistant (SR) subgroups. The underlying mechanisms involved in the SS and SR phenomenon in patients with RA remain unknown but are of considerable therapeutic interest.

THE INFLUENCE OF THE HORMONAL SYSTEM ON PEDIATRIC RHEUMATIC DISEASES

The role of NEI interactions in children with chronic inflammatory rheumatic disorders has not been systematically studied to the same extent as in adults. The data that are currently available suggest that NEI mechanisms are involved in the pathophysiology of some of the diseases. These include JRA, JSLE, and JAS. Prolactin has been most extensively investigated, showing interesting parallels with findings in adult rheumatologic diseases. Limited data on cortisol suggest a deficiency of production in JRA, a situation similar to that in adult RA. These findings suggest that there is a proinflammatory hormonal bias in children with JRA and JSLE. The data in children with chronic autoimmune inflammatory disorders seem to be identical to those seen in adults with RA and SLE, but a clear delineation of the role of the neuroendocrine-immune system in disease pathophysiology is still required. The neuroendocrine aspects of pediatric rheumatologic disease observed to date suggest a number of avenues for further research in the field of neuroendocrine immunology, which may open up novel therapeutic options.

Suppression of inflammation in primary systemic vasculitis restores vascular endothelial function: lessons for atherosclerotic disease?

Chronic inflammatory rheumatic disorders are associated with excess cardiovascular mortality. This may result from arteriosclerosis following inflammatory damage to the vessel wall by vasculitis. Our hypothesis that vasculitis results in arteriosclerosis by causing vascular endothelial dysfunction was tested in patients with primary systemic necrotizing vasculitis (SNV). Endothelial function was assessed in cross-sectional and longitudinal studies of patients with primary SNV by measuring flow-mediated, endothelium-dependent brachial artery vasodilatation. These patients exhibited marked endothelial dysfunction compared with controls. Remission induction in patients with active primary SNV restored endothelial function. Endothelial function is significantly impaired in adults with primary SNV, supporting the hypothesis that premature arteriosclerosis in chronic inflammatory rheumatic disorders results from endothelial dysfunction secondary to vasculitis. Normalization of endothelial function after the treatment of primary SNV suggests that early suppression of disease activity in chronic inflammatory rheumatic disorders may reduce long-term vascular damage. The role of inflammation in atheroma formation is increasingly appreciated; this work raises questions regarding the potential for anti-inflammatory therapy in atherosclerosis itself.