Rheumatoid Arthritis: Aringer M

Aringer M, Leuchten N, Machold KP. · Bereich Rheumatologie, Medizinische Klinik und Poliklinik III, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany. · Z Rheumatol. · Pubmed #18034251 No free full text.

Abstract: Early diagnosis and therapy of persisting (or chronic) polyarthritis is essential for preventing permanent damage. The guidelines of the German Society for Rheumatology recommend referral to a rheumatologist 6 weeks (at the latest) after symptom onset. DMARD therapy should be initiated within 12 weeks. Even earlier, high titer rheumatoid factor, detectable antibodies to CCP, or early erosion, constitute firm arguments for initiating DMARD therapy in patients with arthritis. At this time point, fast acting combination therapy frequently achieves remission or at least low disease activity. Since TNF blockers are not commonly available for first line therapy, corticosteroids should accompany DMARD initiation. Sufficient capacity in early consultation at arthritis clinics, optimized communication with primary care physicians and sensibilisation of the entire population are essential to prevent permanent damage in as many patients as possible.

Cope AP, Schulze-Koops H, Aringer M. · Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London, UK. · Clin Exp Rheumatol. · Pubmed #17977483 No free full text.

Abstract: Rheumatoid arthritis (RA) is one of the most common chronic inflammatory syndromes. As such, RA is often considered the prototype disease for defining both the molecular and pathological basis of immune-mediated chronic inflammatory disease, and for validating targeted therapies. The immunogenetics of RA suggest a key role for aberrant pathways of T-cell activation in the initiation and/or perpetuation of disease. In the T-cell activation process, CD4+ T-cells are engaged by antigenic peptide fragments in a complex with HLA class II molecules, in addition to co-stimulatory molecules, such as CD80/CD86, expressed on the surface of professional antigen presenting cells. The strongest evidence supporting a role for CD4+ T cells in disease pathogenesis is the association between RA and HLA-DRB1; however, the functional role of this association has yet to be defined. Susceptibility to RA may also be linked with several RA-associated allelic variants of genes, especially PTPN22, but also CTLA4, IL2RA, IL-2RB, STAT4, PTPN2 and PADI4, many of which encode molecules directly implicated in pathways of T-cell activation.The presence of inflammatory infiltrates, such as follicular structures, in the synovial membrane provides compelling evidence of ongoing immune reactions in moderate to severe RA. These structures likely play a key role in T cell - B cell cooperation and the local generation of specific autoantibodies; as such, chronically activated synovial T cells represent key cellular targets for therapy. Evidence also supports a role for T-helper (Th) cells, Th17 cells, and impaired CD4+CD25(hi) regulatory T cell (Treg) function in the pathogenesis of RA. In addition to discussing a range of issues regarding T-cell activation in RA, this review describes how therapeutic modulation of T-cell function, as opposed to profound immunosuppression or immunodepletion, has been associated with better disease outcomes in clinical trials. Ultimately, elucidation of the distinct effects of co-stimulation modulation with abatacept on T cells should provide key insights into understanding how to restore immune homeostasis in patients with RA.

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.

Schett G, Herak P, Graninger W, Smolen JS, Aringer M. · Division of Rheumatology, Department of Internal Medicine III, University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. · J Clin Microbiol. · Pubmed #15872306 links to  free full text

Abstract: Listeriosis can be a cause of infectious arthritis. Here, we present a case of articular listeriosis in a patient with rheumatoid arthritis receiving treatment with etanercept, a tumor necrosis factor antagonist. We review the literature of articular listeriosis and discuss the role of tumor necrosis factor blockade in precipitating listeriosis.

Smolen JS, Hayer S, Schett G, Redlich K, Aringer M, Kollias G, Wagner E, Steiner G. · Medical University Vienna. · Autoimmun Rev. · Pubmed #15309784 No free full text.

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Aringer M, Graninger WB. · Division of Rheumatology, Department of Internal Medicine III, University Vienna. · Acta Med Austriaca. · Pubmed #11899752 No free full text.

Abstract: Rheumatoid arthritis (RA) is a serious illness that can only be controlled by the appropriate use of disease modifying anti-rheumatic drugs (DMARDs). In spite of the successful use of such substances, and of methotrexate in particular, a large number of patients still experience disease progression. Leflunomide and the two anti-TNF agents, infliximab and etanercept, were therefore warmly greeted as very welcome additions to the rheumatologist's armamentarium. These successful newcomers, their strengths and problems are the focus of the present review.

Leuchten N, Aringer M. · Medizinische Klinik und Poliklinik III, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Deutschland. · Internist (Berl). · Pubmed #18985308 No free full text.

Abstract: Advances in the therapy of rheumatoid arthritis with disease modifying antirheumatic drugs (DMARD) such as methotrexate and biological response modifiers in particular, have turned a chronic progressive disease with significant invalidity and mortality into one that can be well controlled. To prevent irreversible damage, early diagnosis is essential. DMARD therapy needs to be instituted within three months after symptom onset - a clinical and organisational challenge. Long term DMARD therapy is monitored using standardized scores and modified whenever not sufficiently successful. Analgesia, physiotherapy and occupational therapy as well as orthopaedic surgery play important roles in the management of rheumatoid arthritis. Consequent multimodal therapy can decisively influence the course of the disease and prevent or at least minimize damage.

Aringer M. · Klinische Abteilung für Rheumatologie, Universitätsklinik für Innere Medizin III, Währinger Gürtel 18-20, A-1090 Wien. · Wien Med Wochenschr. · Pubmed #12705062 No free full text.

Abstract: Because of Cyclooxygenase-2 selective non steroidal anti-inflammatory drugs (NSAIDs), the therapy of articular pain has become safer and more convenient. Currently, two highly Cyclooxygenase-2 selective drugs, celecoxib and rofecoxib, are available. Both are effective for patients with osteoarthritis (at daily dosages of 200 mg and 12.5 mg, respectively) and rheumatoid arthritis (RA) (at twice the above dosages). At higher daily dosages of 800 mg and 50 mg these substances still appear safe with regard to life-threatening gastrointestinal complications (perforation, obstruction, bleeding), if not given with concomitant aspirin. However, Cyclooxygenase-2 selective non steroidal anti-inflammatory drugs do not confer protection against platelet aggregation and aspirin must be given where required for cardiovascular prophylaxis. Most patients will then routinely need gastroprotective agents such as proton pump inhibitors or misoprostol; it is unclear whether coxibs confer any benefit under such circumstances. Although not a coxib, Meloxicam does not appear to cause serious gastrointestinal complications if the low daily dosage of 7.5 mg is sufficient for the control of less pronounced pain and thus not exceeded. The gastrointestinal safety of nimesulide can not be sufficiently evaluated based on the available clinical data.

Aringer M, Stummvoll GH, Steiner G, Köller M, Steiner CW, Höfler E, Hiesberger H, Smolen JS, Graninger WB. · Department of Rheumatology, Internal Medicine III, University of Vienna, Austria. · Rheumatology (Oxford). · Pubmed #11511756 links to  free full text

Abstract: OBJECTIVE: To investigate if interleukin-15 (IL-15) (rather than IL-2) is increased in systemic lupus erythematosus (SLE) and might be responsible for immunological abnormalities of SLE such as the increased lymphocytic expression of Bcl-2 and CD25. METHODS: Serum IL-15, IL-2 and tumour necrosis factor (TNF) levels of 65 SLE patients, 20 healthy persons and 10 rheumatoid arthritis (RA) patients were measured by enzyme-linked immunosorbent assay (ELISA). For 25 SLE patients, the percentage of CD25 + lymphocytes and the lymphocytic Bcl-2 levels were simultaneously determined by fluorocytometry. Peripheral blood mononuclear cells (PBMC) of 15 SLE patients were incubated with or without recombinant IL-15 and the influence on Bcl-2 and CD25 was determined. RESULTS: IL-15 was found to be elevated in 25 SLE sera (38%), but in none of the 20 healthy sera (P = 0.0005) and none of the 10 RA sera. Both lymphocyte CD25 and Bcl-2 expression significantly correlated with serum IL-15 and were increased by recombinant IL-15. CONCLUSION: Serum IL-15 may in part be responsible for the immunological abnormalities seen in active SLE.

Stummvoll GH, Aringer M, Machold KP, Smolen JS, Raderer M. · Department of Rheumatology, Internal Medicine III, University of Vienna, Austria. · Scand J Rheumatol. · Pubmed #11252691 No free full text.

Abstract: Recent onset arthritis reminiscent of rheumatoid arthritis (RA) may be an early manifestation of an occult malignancy. In this report, we present two patients with cancer-associated polyarthritis. Both suffered from symmetric polyarthritis when initially visiting their physicians and did not achieve relief when treated with non-steroidal anti-rheumatic drugs (NSAIDs). In both patients, subsequent work-up led to the diagnosis of an underlying malignancy. One patient suffered from small cell lung cancer (SCLC), while the other was diagnosed with adenocarcinoma of the colon. In both, the arthritis spontaneously disappeared after successful treatment of the malignancy, i.e. chemotherapy and tumor resection, respectively. We discuss these cases in view of the existing literature, since awareness of the entity of cancer polyarthritis is necessary for its timely treatment and may potentially be life-saving.

Frucht DM, Aringer M, Galon J, Danning C, Brown M, Fan S, Centola M, Wu CY, Yamada N, El Gabalawy H, O'Shea JJ. · Lymphocyte Cell Biology Section, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892, USA. · J Immunol. · Pubmed #10779770 links to  free full text

Abstract: Stat4 is a key transcription factor involved in promoting cell-mediated immunity, whose expression in mature cells has been reported to be restricted to T and NK cells. We demonstrate here, however, that Stat4 expression is not restricted to lymphoid cells. In their basal state, monocytes do not express Stat4. Upon activation, however, IFN-gamma- and LPS-treated monocytes and dendritic cells express high levels of Stat4. Monocyte-expressed Stat4 in humans is phosphorylated in response to IFN-alpha, but not IL-12. In contrast, the Th2 cytokines, IL-4 and IL-10, specifically down-regulate Stat4 expression in activated monocytes, while having little effect on Stat6 expression. Moreover, macrophages in synovial tissue obtained from patients with rheumatoid arthritis express Stat4 in vivo, suggesting a potential role in a prototypical Th1-mediated human disease. IFN-alpha-induced Stat4 activation in human monocytes represents a previously unrecognized signaling pathway at sites of Th1 inflammation.

Köller M, Aringer M, Kiener H, Erlacher L, Machold K, Eberl G, Studnicka-Benke A, Graninger W, Smolen J. · Division of Rheumatology, Department of Internal Medicine III, University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. · Ann Rheum Dis. · Pubmed #10531076 links to  free full text

Abstract: OBJECTIVE: To determine the presence of adhesion molecules on monocytes/macrophages (Mphi) from peripheral blood (PB) and synovial fluid (SF) in patients with osteoarthritis (OA) and inflammatory joint diseases (rheumatoid (RA) and reactive arthritis (ReA)) in order to improve our understanding of the possible mechanisms underlying the inflammatory process. METHODS: Whole blood and SF cells were stained with monoclonal antibodies against CD11a (LFA-1), CD15 s (sialyl-Lewis X), CD44, CD54, VLA-4, and HLA-DR counterstained with anti-CD14 antibodies as a Mphi marker for dual fluorescence analysis by flowcytometry. RESULTS: On PB-Mphi, CD15s was markedly increased in both RA as well as ReA compared with OA. Furthermore, in the PB LFA-1, CD44, and HLA-DR showed a higher surface density on Mphi in ReA than in OA. Comparison between SF and PB showed significantly higher CD44 and CD54 expression on SF-Mphi. These molecules play an important part in lymphocyte-Mphi interaction. CONCLUSION: In PB from patients with inflammatory joint diseases, Mphi are activated, allowing recruitment into the synovial compartment. These disorders, in contrast with OA seem to be "systemic" in nature. Within the SF, different adhesion molecules are expressed on CD14(+) Mphi as compared with PB.