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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Recently, a new study has identified a couple of biomarkers that may predict disease progression in patients suffering from ankylosing spondylitis (or: AS for short), an autoimmune disease also called Morbus Bechterew.
The German study describes key inter-group differences between different types of AS patients, which may predict the progression of structural damage in the spine. In the future awareness of such differences will help physicians to stratify patients due to risk. Hence, the results may pave the way for developing specific treatment options for this autoimmune disorder.
New treatment options on the horizon
In the more recent past, several biomarkers have been described to be associated with radiographic spinal progression and syndesmophyte formation in Bechterew’s disease. However, it is not clear, whether these biomarkers are also able to predict new bone formation in AS patients.
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…)
In rheumatoid arthritis, standard heart disease risk tools underrate danger!
Patients suffering from rheumatoid arthritis, or RA for short, are at higher risk for heart disease. Among experts that’s a matter of common knowledge (fortunately and increasingly that is basic knowledge among patients, too!).
Watch out, doctors! – In elderly rheumatoid arthritis patients commonly used heart disease risk assessment tools regularly fail, according to a current study. – © Robbie Ribeiro
On a less positive note, commonly used heart disease risk assessment tools seem to be inadequate for estimating the risk of cardiovascular disease danger faced by RA patients. That is what a brand-new study found.
In this blog article I summarise the main results of the research done at Mayo Clinic in Rochester, Minnesota (USA). The study is entitled Usefulness of Risk Scores to Estimate the Risk of Cardiovascular Disease in Patients With Rheumatoid Arthritis, and it has been published online on 20th April 2012 in The American Journal of Cardiology.
Heart disease risk in RA: More accurate assessment tools needed
The study estimated the accuracy of the Framingham and Reynolds risk scores, two tools commonly used by physicians for assessing patients’ heart disease danger. The scientists found that these two assessment tools substantially underrated cardiovascular disease danger both in women and men suffering from rheumatoid arthritis. In particular, that happens in older patients. Interestingly enough, it also happens in people who test positive for rheumatoid factors. (more…)
Anti-CCP hs (high sensitive)®: a new biomarker for the serological diagnosis of early rheumatoid arthritis
Timely diagnosis is of critical importance to the progression of rheumatoid arthritis (RA) because the rapid implementation of intensive treatment can inhibit damage to the joints and maintain function. In conjunction with medical history, clinical examination, and imaging procedures, serological tests form the foundation for an early diagnosis.
In addition to rheumatoid factors, autoantibodies against citrullinated antigens (ACPA) have proven to be valuable tools for the serological diagnosis of early RA. They have become a critical component of the new 2010 ACR criteria for the classification of RA, and account for three of the six points required to verify a diagnosis of RA. (more…)
The GRÜNER CLUB AUTOIMMUN blog featured a fine post about the history of indirect immunofluorescence. In that article my Austrian colleague Barbara Fabian, community manager of GRÜNER CLUB AUTOIMMUN, described in great detail how indirect immunofluorescence technology, or: IFT, and also referred to as IIF assay, has become an indispensible tool of autoimmune disease diagnostics over the last two decades, and how IFT has become a standard laboratory technique used in serological autoimmune diagnostics.
Without further ado I have translated Barbara’s post in order to make you this text, and especially the interesting images, available. – Here it is:
The Development of Indirect Immunofluorescence Technology (IFT)
by Barbara Fabian, MSc, Community Manager of GRÜNER CLUB AUTOIMMUN
Over the last 20 years, the detection of autoantibodies has developed into an indispensible component of autoimmune diagnostics. Along with serological and clinical data, autoimmune status has become an important building block in the formation of diagnoses. (more…)