Rheumatoid Arthritis: Austria

Stuhlmeier KM. · Ludwig Boltzmann Institute for Rheumatology and Balneology, Vienna, Austria. · Wien Med Wochenschr. · Pubmed #17160372 No free full text.

Abstract: HA takes part in a surprisingly large number of biological processes such as embryogenesis, angiogenesis, cell motility, wound healing and cell adhesion. While substantial progress in HA research has indeed been made over the last years, many important questions have not yet been answered. One of the most pertinent questions awaiting an answer is the quest for functional differences of HA synthesized by the three HAS genes. Of similar importance would be investigations into intracellular signaling pathways involved in the activation of this gene family, a field in which to date very little is known. A better understanding of functional differences between the HAS encoding genes not only holds the promise for a better understanding of a series of biological processes but also the opportunity for selective intervention in a number of maladies characterized by abnormalities of HA levels.

Aletaha D, Smolen JS. · Department of Rheumatology, Medical University of Vienna, Vienna, Austria. · Clin Exp Rheumatol. · Pubmed #17083763 No free full text.

Abstract: A state of remission can be achieved in more and more rheumatoid arthritis (RA) patients. The combination of several RA disease activity measures seems to be important to provide an overall view of disease activity. Remission can be defined by two different approaches: one using a categorical model, requiring criteria for multiple variables to be fulfilled, each with its own threshold value (remission "criteria"); the other using a dimensional model, providing single measures of activity, which allow definition of remission by a single cut point (remission cut points for composite indices). The face validity of remission as defined by composite indices surpasses the one for the "criteria". Likewise, the ones that are not weighted seem to surpass the weighted ones, as can be seen by the significant proportion of patients that continues to have considerable swollen joint counts despite being in Disease Activity Score (DAS)-28 remission. All composite indices seem to perform similarly well as tests for remission using expert judgments as the gold standard.

Smolen JS, Aletaha D. · Department of Rheumatology, Medical University of Vienna; Second Department of Medicine, Lainz Hospital, Vienna, Austria. · Clin Exp Rheumatol. · Pubmed #17083756 No free full text.

Abstract: Remission should be the treatment aim in management of rheumatoid arthritis (RA) today because joint damage may progress in RA patients with low disease activity but presumably does not progress in patients in clinical remission. However, stringent criteria are needed to define remission status, as some criteria in current use allow for considerable residual disease activity. Even using stringent criteria, remission is achievable in a sizable proportion of patients in clinical trials and practice. Defining remission requires an additional consideration: Should a patient who is receiving medication be regarded as in remission if disease is absent, or must the patient be off treatment to be considered to be in remission? A case is made for aiming for a definition of remission that includes patients who continue medication therapy.

Schett G, Hayer S, Zwerina J, Redlich K, Smolen JS. · Medical University of Vienna, Austria. · Nat Clin Pract Rheumatol. · Pubmed #16932627 No free full text.

Abstract: Chronic inflammation and bone loss are closely linked pathophysiologic events. The most typical example of inflammatory bone loss is seen in patients with rheumatoid arthritis who develop systemic osteopenia as well as local breakdown of bone in the direct vicinity of inflamed joints. Understanding the mechanisms of arthritic bone degradation is crucial for designing therapies that can specifically protect joints from structural damage. Since osteoclast differentiation and activity are key events in arthritic bone damage, the signals that trigger osteoclastogenesis are potential therapeutic targets. Receptor activator of nuclear factor-kappaB (RANK) is activated by its ligand, RANKL, an essential molecule for osteoclast development: in the absence of RANKL or RANK, osteoclast differentiation from monocyte precursors does not occur. RANKL is expressed on T cells and fibroblasts within the synovial inflammatory tissue of patients with RA and its expression is regulated by proinflammatory cytokines. In animal models of arthritis, blockade of RANKL-RANK interactions, or a genetic absence of RANKL or RANK, protects against joint damage despite the presence of joint inflammation. Therefore, inhibition of RANKL is regarded as a promising future strategy for inhibiting inflammatory bone loss in patients with chronic inflammatory arthritis.

Smolen JS, Maini RN. · Division of Rheumatology, Medical University of Vienna, Vienna, Austria. · Arthritis Res Ther. · Pubmed #16899109 No free full text.

Abstract: The therapeutic success of biological agents, especially the tumour necrosis factor (TNF) inhibitors, has opened a new chapter in the book of therapies for rheumatoid arthritis. Nevertheless, more than 50% of patients may not respond by > 50% improvement. New compounds have recently entered the treatment arena. One of these is rituximab, which depletes B cells, and another, abatacept, interferes with T-cell co-stimulation. However, although these agents may be effective in a number of patients who fail to respond to TNF blockade, they only rarely induce remission and overall 50% response rates do not exceed those with the TNF inhibitors. Among the major proinflammatory cytokines, IL-6 plays a pleiotropic role both in terms of activating the inflammatory response and osteoclastogenesis. Here, we review recent phase II trials of tocilizumab, a humanized anti-IL-6 receptor antibody that achieves a significant therapeutic response rate.

Machold KP, Nell VP, Stamm TA, Smolen JS. · Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. · Arthritis Res Ther. · Pubmed #16719936 links to  free full text

Abstract: There is increasing evidence for beneficial effects of early DMARD (disease-modifying antirheumatic drug) therapy over delayed treatment in patients who present with arthritis of recent onset. However, no universal consensus exists concerning the choice of initial drug or whether single drugs or combinations should be given as initial treatments. Recent studies have focused on the benefits of various strategies in which treatments were tailored to achieve low levels of disease activity, as assessed using validated response criteria. These studies demonstrated superiority of 'aggressive' over 'conventional' approaches. Whether the inclusion of tumour necrosis factor antagonists or other biologic targeted therapies in such strategies confers additional benefits in terms of improved long-term outcomes must be clarified by further studies. Assessment of risks in the individual patient, allowing individual 'tailoring' of the initial treatment, would be desirable.

Peloschek P, Langs G, Valentinitsch A, Bubale M, Schlager T, Müller-Mang C, Kainberger F. · Klinik für Radiodiagnostik, Medizinische Universität Wien, Währinger Gürtel 18-20, 1090 Wien, Osterreich. · Radiologe. · Pubmed #16715225 No free full text.

Abstract: The need of clinical sciences to measure therapy effects on chronic illness led to development, evaluation, and publication of several radiological methods to monitor disease progression of rheumatic diseases. This review article explains the basics and background of scoring and measurement. The radiologist thus learns to report more compactly and to communicate the results more specifically.

Klauser AS, Moriggl B, Duftner C, Smekal V, Pallwein L, Mur E, Schirmer M. · Universitätsklinik für Radiodiagnostik, Klinische Abteilung für Radiodiagnostik II, Medizinische Universität Innsbruck, Anichstrasse 35, 6020 Innsbruck, Osterreich. · Radiologe. · Pubmed #16715223 No free full text.

Abstract: High-frequency sonography enables excellent detection of early erosions and synovial proliferations. Power Doppler sonography (PDUS) allows for an improved characterization of articular and peritendinous augmented volume, because detection of hypervascularity correlates with inflammatory activity and further is helpful in differentiation from effusion and inactive pannus. The use of contrast media improves the sensitivity of vascularity detection, because they allow for a delineation of vessels at the microvascular level. This is of increased interest, as the development of new therapeutic options targeting the microvascular level calls for earlier diagnosis and optimal assessment of disease activity. Because of good availability, cost effectiveness, and patient acceptance, sonography facilitates early diagnosis of synovial proliferations and erosions as well as therapy follow-up.

Uffmann M. · Klinik für Radiodiagnostik, Medizinische Universität, Währinger Gürtel 18-20, A-1090 Wien, Osterreich. · Radiologe. · Pubmed #16583201 No free full text.

Abstract: Extra-articular manifestations of rheumatoid arthritis are gaining in importance both in rheumatology and other specialities. This report provides information on various organ manifestations and interactions between mere disease-related symptoms and therapeutic effects. Diagnostic radiology plays a crucial role in finding the diagnosis, planning and monitoring of treatment, early detection of complications and drug-related adverse events.

Machold KP, Nell V, Stamm T, Aletaha D, Smolen JS. · Department of Rheumatology, Internal Medicine III, Vienna Medical University, Austria. · Curr Opin Rheumatol. · Pubmed #16582693 No free full text.

Abstract: PURPOSE OF REVIEW: This review provides novel and updated information on pathogenesis, referral, and clinical characteristics as well as therapeutic approaches in early rheumatoid arthritis. RECENT FINDINGS: Early referral is important, but new classification criteria for early rheumatoid arthritis need to be elaborated. Predictive markers for rheumatoid arthritis are still confined to autoantibodies; respective algorithms have been presented. Other biomarkers will still have to prove their usefulness. Magnetic resonance imaging and sonography do not appear to sufficiently distinguish between early rheumatoid and nonrheumatoid arthritis. Rheumatoid arthritis has become milder at presentation in recent years. In its very early stages, the cytokine profile reflects T-cell activation and switches to abundant proinflammatory cytokines thereafter. Disease-modifying antirheumatic drugs plus glucocorticoids are highly effective, as is early use of tumor necrosis factor blockers plus methotrexate. Tight control of disease activity and subsequent therapeutic adjustments are highly effective. Disease activity indices that are simple to calculate have been presented and validated. Early intensive therapy may lead to decrease in disability and cost reduction in rheumatoid arthritis. SUMMARY: Understanding of early arthritis is increasing, especially in prognostic and therapeutic respects, and new treatment strategies appear to improve the outcome in patients with early arthritis. Nevertheless, much remains to be studied to better address the issue of early rheumatoid arthritis.

Aletaha D, Smolen JS. · Department of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria. · Rheum Dis Clin North Am. · Pubmed #16504819 No free full text.

Abstract: This article focuses on measures that are used to evaluate disease activity, damage, and function in three major inflammatory musculoskeletal disorders. The instruments used in rheumatoid arthritis, where most of the methodologic work has been done, are extensively discussed and instruments for the respective domains in psoriatic arthritis and ankylosing spondylitis are likewise presented.

Machold K, Nell V, Aletaha D, Smolen J, Stamm T. · Klinische Abt. für Rheumatologie, Universitätsklinik für Innere Medizin III, Wien. · Z Rheumatol. · Pubmed #16496075 No free full text.

Abstract: Disease activity scores for rheumatoid arthritis have been developed and validated in recent years. They allow the longitudinal documentation of the effectiveness of treatment. Application of these scores in routine daily practice could significantly improve the effectiveness of therapy with relatively little effort. This review presents evidence for the benefits of the application disease activity scores in clinical routine.

Aletaha D, Stamm T, Smolen J. · Klinische Abt. für Rheumatologie, Universitätsklinik für Innere Medizin III, Wien. · Z Rheumatol. · Pubmed #16496073 No free full text.

Abstract: Rheumatoid arthritis (RA) is the most common systemic inflammatory joint disease. It can be treated effectively with disease modifying antirheumatic drugs, and the currently propagated treatment strategy is to treat RA consequently, and revise the therapeutic approach frequently on the basis of proper disease activity evaluation. In the current review, we focus on the instruments and measures used in the assessment of RA disease activity. We will first consider the so-called core set measures of activity, prividing comprehensive overviews on joint count scales, global scales, pain scales, biomarkers, and functional assessment instruments. The second part of the review focuses on the value of composite measures of disease activity; a term under which we subsume activity indices using various formulae, self-assessment tools of disease activity, and response criteria. Among the inflammatory rheumatic diseases, RA is the one for which the most intensive research is done, and usually instruments that work for RA are further tested for other joint diseases. However, there is still a research agenda for the assessment of disease activity, even for RA. One important aspect is to assess the reliability and utility of all available instruments, including the very low end of disease activity, since remission has become an achievable goal. Another focus of disease activity assessment is to derive measures that work in clinical trials and in daily practice, but are also well understood by patients and physicians.This will further improve our ability to care for patients with RA consequently.

Brezinschek HP, Brickmann K, Yazdani-Biuki B, Dörner T, Graninger WB, Brezinschek RI. · Rheumatic Diseases Division, Department of Internal Medicine, Medical University Graz, Graz, Austria. · Wien Med Wochenschr. · Pubmed #16465615 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent inflammation of synovial tissue. Although the initiating event of RA is still unknown, recent research has demonstrated the importance of the increased production of tumor necrosis factor (TNF) alpha in the perpetuation of the inflammatory process of this disease. Targeting this molecule with soluble receptors, i.e., etanercept, or antibodies, like infliximab or adalimumab, a new class of highly effective anti rheumatic drugs has been developed. Unfortunately, not all patients respond sufficiently to TNF blockade and some of the patients become unresponsive to TNF-blocking agents. Targeting B-lymphocytes in these patients has opened a new therapeutic window. It has been demonstrated that B-lymphocytes have an important impact in the pathophysiology of RA. These cells produce not only a variety of autoantibodies, but directly stimulate autoaggressive T lymphocytes in the synovium. Furthermore, B-lymphocytes produce a variety of proinflammatory cytokines that also activate monocytes and synoviocytes. Several placebo-controlled clinical trials have demonstrated the efficacy of B-lymphocyte-directed therapy in patients that have responded poorly to conventional disease-modifying drugs or TNF blockade. In addition, several other B-cell specific antigens are potential targets in different autoimmune diseases.

Köller MD. · Department of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria. · Wien Med Wochenschr. · Pubmed #16465614 No free full text.

Abstract: The approach of targeting cytokines has dramatically improved the success in the treatment of rheumatoid arthritis (RA). The blocking of tumor necrosis factor (TNF)-alpha or interleukin (IL)-1 is well established in clinical practice, but a lack or loss of clinical response still occurs in up to 30% of RA patients. Therefore, enhanced efforts must be made to develop new strategies to disrupt the inflammatory process and to inhibit synovitis and joint destruction. In this respect, the blocking of IL-6 receptor with tocilizumab, the prevention of costimulatory T cell signals by abatacept, or targeting B cells with rituximab look promising in clinical trials. Furthermore, blocking intracellular signal transduction broadens the spectrum of targeted therapy. This article reviews recent clinical aspects of established anti-cytokine therapies and gives an insight into the experimental and clinical development of new specifically acting drugs.

Wada T, Nakashima T, Hiroshi N, Penninger JM. · Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Dr. Bohrgasse 3, A-1030 Vienna, Austria. · Trends Mol Med. · Pubmed #16356770 No free full text.

Abstract: Hundreds of millions of people worldwide are affected by bone-related diseases, such as osteoporosis and rheumatoid arthritis. Understanding the molecular mechanisms of bone metabolism is crucial for developing novel drugs for treating such diseases. In particular, genetic experiments showing that the receptor activator of NF-kappaB (RANK), its ligand RANKL, and the decoy receptor OPG are essential, central regulators of osteoclast development and osteoclast function were significant turning points in our understanding of bone diseases. RANKL-RANK signaling activates a variety of downstream signaling pathways required for osteoclast development. Moreover, molecular cross-talk between RANKL-RANK and other ligand-receptor systems fine-tunes bone homeostasis in normal physiology and disease. Designing novel drugs that target RANKL-RANK and their signaling pathways in osteoclasts could potentially revolutionize the treatment of many diseases associated with bone loss such as arthritis, tooth loss, cancer metastases or osteoporosis.

Wagner EF, Eferl R. · Research Institute of Molecular Pathology (IMP), Vienna, Austria. · Immunol Rev. · Pubmed #16313345 No free full text.

Abstract: The skeleton and the immune system share a variety of different cytokines and transcription factors, thereby mutually influencing each other. These interactions are not confined to the bone marrow cavity where bone cells and hematopoietic cells exist in proximity but also occur at locations that are target sites for inflammatory bone diseases. The newly established research area termed 'osteoimmunology' attempts to unravel these skeletal/immunological relationships. Studies towards a molecular understanding of inflammatory bone diseases from an immunological as well as a bone-centered perspective have been very successful and led to the identification of several signaling pathways that are causally involved in inflammatory bone loss. Induction of receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) signals by activated T cells and subsequent activation of the key transcription factors Fos/activator protein-1 (AP-1), NF-kappaB, and NF for activation of T cells c1 (NFATc1) are in the center of the signaling networks leading to osteoclast-mediated bone loss. Conversely, nature has employed the interferon system to antagonize excessive osteoclast differentiation, although this counteracting activity appears to be overruled under pathological conditions. Here, we focus on Fos/AP-1 functions in osteoimmunology, because this osteoclastogenic transcription factor plays a central role in inflammatory bone loss by regulating genes like NFATc1 as well as the interferon system. We also attempt to put potential therapeutic strategies for inflammatory bone diseases in perspective.

Aletaha D, Smolen J. · Department of Rheumatology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. · Clin Exp Rheumatol. · Pubmed #16273793 No free full text.

Abstract: Composite indices or pooled indices are useful tools for the evaluation of disease activity in patients with rheumatoid arthritis (RA). They allow the integration of various aspects of the disease into a single numerical value, and may therefore facilitate consistent patient care and improve patient compliance, which both can lead to improved outcomes. The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI) are two new tools for the evaluation of disease activity in RA. They have been developed to provide physicians and patients with simple and more comprehensible instruments. Moreover, the CDAI is the only composite index that does not incorporate an acute phase response and can therefore be used to conduct a disease activity evaluation essentially anytime and anywhere. These two new tools have not been developed to replace currently available instruments such as the DAS28, but rather to provide options for different environments. The comparative construct, content, and discriminant validity of all three indices--the DAS28, the SDAI, and the CDAI--allow physicians to base their choice of instrument on their infrastructure and their needs, and all of them can also be used in clinical trials.

Smolen JS, Aletaha D, Keystone E. · Medical University of Vienna and Lainz Hospital, Vienna, Austria. · Arthritis Rheum. · Pubmed #16200577 links to  free full text

This publication has no abstract.

Sautner J, Leeb BF. · II. Medizinische Abteilung, Niederösterreichisches Kompetenzzentrum für Rheumatologie, Humanisklinikum NO, Landstrasse 18, 2000 Stockerau, Austria. · Internist (Berl). · Pubmed #16195863 No free full text.

Abstract: Rheumatoid arthritis potentially causes joint destruction, organ failures, and accompanying disorders. Therefore initiating therapeutic measures as early as possible is crucial, whereby symptomatic treatment only is definitely insufficient. Among the traditional disease-modifying antirheumatic drugs (DMARD) Methotrexate is regarded the gold standard. Increasing knowledge of cell-interactions, particularly of the cytokine-cascade, resulted in new therapeutic options. Direct impact via "biologicals" on key inflammatory mediators, primarily TNF-alpha, offers the possibility of effectively modulating or even arresting disease progression. Nowadays, those substances are applied in non-responders to traditional DMARD. Despite their benefits, cons like an increased risk for infections, for exacerbating latent tuberculosis and possibly for malignancies must be considered. Thus, a thorough patient check-up before initiating these therapies is mandatory. Pharmacoeconomic aspects influence the discussion about these "new therapies". The high costs of biologicals, however, should be related to the possible reduction of the diseases psychological, social and economic burdens.

Schett G, Smolen JS. · Division of Rheumatology, Department of Internal Medicine III, University of Vienna, Vienna, Austria. · Curr Pharm Des. · Pubmed #16178762 No free full text.

Abstract: In chronic arthritis synovial inflammation is usually accompanied by bone erosion. Due to resulting structural damage, bone erosion is major reason for disability of RA patients. Thus, drug therapy in arthritis is not only focussed on the control of synovial inflammation but also on preserving bone from structural damage. Bone erosion in arthritis is a consequence of synovial osteoclast formation. Therapeutic approaches, which interfere with synovial osteoclastogenesis and/or osteoclast activation, are therefore of great interest. This review describes the pathomechanism of arthritic bone erosion, describes its cellular and molecular players and gives insights in current therapeutic tools to inhibit this process. Effects of blockade of tumor necrosis factor, interleukin-1 and receptor activator of NF-kB ligand are discussed. Arthritis and bone loss are two related conditions but they are not necessarily linked to each other. Thus, in case of short-lasting and self-limited disease, structural damage is highly unusual. One of the most intriguing examples is viral arthritis, which as in case of parvovirus infection is a polyarticular disease closely mimicking rheumatoid arthritis. However, parvoviral arthritis is always a self-limited condition and resolves without any structural damage. In contrast, chronic forms of arthritis, such as psoriatic arthritis or rheumatoid arthritis (RA) are usually destructive and lead to alteration of joint structure and functional impairment.

Smolen JS, Redlich K, Zwerina J, Aletaha D, Steiner G, Schett G. · Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Austria. · Clin Rev Allergy Immunol. · Pubmed #16129908 No free full text.

Abstract: Therapy of rheumatoid arthritis (RA) aims at interfering with the disease process, namely inflammation and destruction of the joints, and thus at preventing long-term disability. Proinflammatory cytokines play a decisive role in the generation of the inflammatory and destructive response. Aside from traditional disease-modifying anti-rheumatic drugs and tumor necrosis factor-blocking agents, a number of targeted therapies are currently in evaluation, such as abatacept (interfering with co-stimulation), rituximab (an anti-B-cell agent) and tocilizumab (an anti-interleukin-6 receptor antibody). In phase II trials, all these agents have resulted in significant clinical improvement, and phase III trials have been partly completed with similar results and are partly on the way. Because none of these agents lead to good clinical responses in all patients and many patients have only relatively low degrees of response, it will still be a challenge to find the best therapeutic paths to combat the "inflammatory house of cards" of RA.

Trieb K. · University of Vienna, Austria. · J Bone Joint Surg Br. · Pubmed #16129737 No free full text.

This publication has no abstract.

Zwerina J, Redlich K, Schett G, Smolen JS. · Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. · Ann N Y Acad Sci. · Pubmed #16127012 No free full text.

Abstract: Although considerable progress has been made by adequate treatment with traditional disease-modifying antirheumatic drugs (DMARDs), therapy of rheumatoid arthritis (RA) still remains difficult. The discovery of the importance of cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-15 (IL-15), which are also stimulated by consequences of autoimmune responses, has led to the development of anticytokine therapies ("biologicals"). Blocking TNF or also, to some extent, IL-1 has proved beneficial in DMARD-resistant RA patients in multiple clinical trials. Along with clinical improvement, TNF blockade has been shown to halt radiographic disease progression, a major risk factor for disability. Recently, clinical trials have shown a significant therapeutic benefit of biological inhibitors of IL-6, and also of IL-15, with an efficacy comparable to that of TNF blockers. All these agents are particularly efficacious when combined with methotrexate. Although clinical remission is difficult to achieve even with anticytokine treatment, these drugs offer the potential to decrease disease activity and improve quality of life in a majority of RA patients, and it is conceivable that combinations of biological therapies may pave the path to even better success, which ultimately is remission or even cure.

Aringer M, Steiner G, Smolen JS. · Department of Rheumatology, Internal Medicine III, Medical University of Vienna, AKH, Waehringer Guertel 18-20, A-1090 Vienna, Austria. · Rheum Dis Clin North Am. · Pubmed #16084315 No free full text.

Abstract: For patients who have combined features of rheumatoid arthritis, the limited cutaneous form of systemic sclerosis, and inflammatory myopathies, the concept of mixed connective tissue disease (MCTD) often helps to predict and diagnose organ problems and to educate the patient accordingly. With high titer IgG antibodies to U1 ribonucleoprotein (U1-snRNP), this concept is supported by a specific serologic marker, and autoantibodies to U1-snRNP and to heterogeneous nuclear ribonucleoprotein (hnRNP)-A2 display MCTD specificity with regard to the recognized epitopes. In addition, the association of MCTD with HLA-DR4 distinguishes it from systemic erythematosus lupus and systemic sclerosis, and speaks to its being a disease entity, rather than a mixture of yet undifferentiated collagen vascular diseases. The authors believe that the concept is useful in daily practice and accurate in the idea that MCTD constitutes a disease entity of its own.