Towards Early diagnosis and biomarker validation in Arthritis Management
EuroTEAM Arthritis (Towards Early diagnosis and biomarker validation in Arthritis Management) is a challenging research project, funded by the European Union with 5.77 Million Euro for four years. Clinicians and lab scientists with world class expertise in rheumatoid arthritis research from 13 renowned European research institutions and three industrial partners with competence in design and development of diagnostic test kits for autoimmune diseases, local gene therapy for rheumatic diseases, and human genome analysis join their efforts in the discovery of novel biomarkers for early detection of rheumatoid arthritis. The EuroTEAM members intend to develop approaches to predict the onset of rheumatoid arthritis in people who do not yet have the disease. Ultimately, this will help in the development of treatments to prevent people from getting rheumatoid arthritis.
Rheumatoid factor (RF) is one of the best known serological markers in rheumatology – development of the test dates back into the 1940ies. Since this time the toolkit of serological diagnostic tests for rheumatoid arthritis (RA) has been complemented by the more specific anti-citrullinated protein antibody (ACPA) tests. However, none of the various ACPA tests has completly replaced RF until now.
The jigsaw puzzle of rheumatoid arthritis classification
In contrast, the significance of RF has been further substantiated with the definition of the 2010 ACR criteria for classification of RA. Moreover, recent studies have shown the potential of RF as a contributor to disease pathogenesis.
The famous musician Seal is known for his numerous international hits, and for living with an autoimmune disease: the scars on his face are the result of discoid lupus erythematosus. Picture: C. Grube for Access2music.de, wikimedia
Systemic lupus erythematosus (SLE) is a chronic inflammatory disease with manifold manifestations. SLE belongs to the family of autoimmune disorders, diseases that occur, when a mislead immune system attacks the body’s own structures. SLE can affect almost any organ system, thus its presentation and course are highly variable, and diagnosis and therapy may be challenging.
With the intention to classify SLE patients for research and surveillance studies and to support clinicians in confirming a diagnosis, a set of clinical and laboratory classification criteria has been developed and released by the American College of Rheumatology (ACR). The first classification criteria for SLE were originally published in 1971 [1,2]. They have been updated 1982  and 1997  to incorporate new immunologic knowledge and improve patient classification. In contrast to the 1987 criteria, the 1997 criteria have not been validated.
The most recent addendum to the classification criteria for SLE dates from 2012, when the Systemic Lupus International Collaborating Clinics (SLICC) group published a revision and validation of the ACR criteria .
Anti-Centromere B on HEp2 cells
HEp2 cells are held dear in autoimmune diagnostics. They are invaluable for people engaged in analysing autoantibodies, as E. coli is for molecular biologists or mice for toxicologists.
In spite of a wide range of other suitable methods and technologies, determination of autoantibodies with indirect immuno-fluorescence assays (IFA) on human epithelioma (HEp2) cells still contributes significantly to the diagnosis of autoimmune diseases. The widely recognised advantages of this method are high sensitivity and a broad spectrum of antibodies that can be analysed simultaneously. In addition to mere detection of antibodies a characteristic fluorescence pattern and staining of metaphase and cytoplasmic cells offer supplementary information.
When an autoimmune disease is suspected, the HEp-2 test usually is the first line test. Any positive result is then followed up by a step-wise diagnostic approach, including other immunological tests like ELISA (enzyme-linked immunosorbent assay) for single antibody specificities or immunoblot tests.
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The web community GRÜNER CLUB AUTOIMMUN is a voluntary association of scientists, laboratory specialists, medical doctors, students and immunofluorescence enthusiasts from Austria. In their internet blog these experienced IFT professionals discuss questions, ideas and concepts of immunofluorescence tests in autoimmune disease diagnostics.
In a recent posting my Austrian colleague Barbara Fabian, community manager of GRÜNER CLUB AUTOIMMUN, refered to the relationship between the formation of autoantibodies against glomerular basal membrane (GBM) and ANCA (antibodies against cytoplasmic antigens of neutrophil granulocytes). The article was originally written in German language, but we had it translated for the not German speaking readers of the Autoimmunity Blog.
Autoantibodies against Glomerular Basal Membrane and Myeloperoxidase in Crescentic Glomerulonephritis
by Barbara Fabian, Vienna
Crescentic Glomerulonephritis (CGN) is an autoimmune disease of the kidney that leads to vasculitis of the capillaries in the glomeruli. The appearance of characteristic autoantibodies or antibody complexes is indicative of CGN and allows for the differentiation of three groups:
Linking autoantibody production to bone loss
in rheumatoid arthritis
Autoantibodies against citrullinated proteins (ACPA) are found in people with rheumatoid arthritis and are one of the strongest risk factors for bone destruction in this disease. A recent study now directly links the formation of antibodies binding to mutated citrullinated vimentin (anti-MCV) to bone loss in rheumatoid arthritis, indicating that these autoantibodies act on osteoclasts, the bone cells responsible for bone resorption.
Harre U, Georgess D, Bang H, Bozec A, Axmann R, Ossipova E et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J Clin Invest 2012; 122(5):1791-802. (1)
The research of U. Harre, G. Schett and their coworkers provides fundamental new insights into the interaction between bone and the immune system in the inflammatory process leading to the development of rheumatoid arthritis.
Since the early 1960s almost a dozen different criteria for Sjögren’s syndrome (SS) have been published, both for classifying and for diagnosing that autoimmune disease. Recently, an international team of rheumatologists has published new classification criteria for Sjögren’s syndrome. In the April issue of the Arthritis Care & Research journal the authors propose clear and carefully worded guidelines.
Without question, these “new 2012 classification criteria for Sjögren’s syndrome” are urgently needed to better support etiologic and genetic research and therapeutic trials for Sjögren’s syndrome. Indeed, the new criteria are the first to be based solely on objective clinical tests!
Many other criterions have permitted various testing subjectivity to enable the classification of the disorder. In consequence, subjectivity has made standardisation of clinical trial inclusion something of a moving target, limiting comparability of research data across studies and impeding the needed robust clinical evaluation of possible new treatments. But criteria used for enrollment into clinical trials need to be clear, be easy to apply. And the new 2012 criteria agree to that demand. (more…)
Celiac disease diagnostics revised
Anti-endomysial antibodies on monkey esophagus
The diagnostic criteria for celiac disease (CD) have remained unchanged for more than 20 years, after the 1990 revision of the guidelines originally formulated in 1969. During this period the disease has been intensively studied and scientific findings have unveiled the genetic background of celiac disease, linked to the human leukocyte antigen (HLA)-DQ2 and HLA-DQ8 haplotypes. The key autoantigen tissue transglutaminase (tTG) has been identified and reliable laboratory tests for disease specific autoantibodies now contribute to diagnostics and complement the methodological repertoire of clinical observations and histologic findings in duodenal biopsy samples. Finally, the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) has now published New Guidelines for the Diagnosis of Celiac Disease.
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Liver Disease Diagnostics: Antibody-Based Diagnosis of Autoimmune Liver Disease
For the launch of our Liver-9-Line immunoblot test (to our press release “Liver Disease Diagnostics by Immunoblot” of May 16, 2011), I dug through a pile of literature on the topic of autoantibody-based diagnosis of autoimmune diseases of the liver. In the last week I picked it all up again and worked through it systematically.
The interior surface of the liver. A reproduction of a lithograph plate from Gray’s Anatomy.
The reason for my renewed interest is that we brought four more ELISA tests for liver diagnostics to the market two weeks ago. They are the Anti-LKM-1, Anti-SLA, Anti-gp210, and Anti-Sp100 tests, all designed for fully automated autoimmune diagnosis with our Alegria system. All four test systems assist the formulation of a diagnosis when autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) are suspected, or for differential diagnosis when another disorder of the liver is assumed. (more…)
Mobile Health Applications and Their Significance for Medical Education and Healthcare
As we here at ORGENTEC Diagnostika set about developing a smartphone application for our company in mid-September of this year, we had no idea what an exciting field we were entering.
We were also amazed when we began to intensively explore the iTunes App store and Android Market to see “what the others were up to”. We tried out many things, looked at a large variety of very different apps, and loaded our iPhones up with a broad range of apps.
The ORGENTEC Autoimmunity Guide: Three screenshots of our company’s mobile medical app on autoimmunity, autoimmune disorders, and autoimmune diseases diagnostics. – © ORGENTEC Diagnostika, Mainz
We also researched a lot of technical details, reading this blog and that. We learned a great deal about the market shares of the individual mobile operating systems (“Who is winning the race for domination on the mobile operating system market in which corner of the world? Apple’s iOS or the Android OS? Blackberry’s RIM or Windows Phone 7?”). We thus also had to involve ourselves to some extent in some “religious wars” (“iPhone or Android device?” – … there’s no question, is there?). (more…)