[The pathogenic and clinical significance of the RANK-RANKL-osteoprotegerin system in rheumatoid arthritis]


DECEMBER 23, 2011

LAM KID - 2011;1(03)

[Rheumatoid arthritis (RA) is characterised by increased local and generalised bone resorption, which manifests in the develoment of marginal erosions and generalised osteoporosis, respectively. An increasing number of data suggest that lymphocytes, proinflammatory cytokines and other mediators involved in inflammation contribute to arthritic bone resorption. Therefore, the term ‘osteoimmunology’ has also become widely used. In RA, Receptor Activator of Nuclear Factor kappa B (RANK) and its ligand (RANKL) play a crucial role in bone resorption. These proteins, which belong to the tumor necrosis factor a (TNF-a) receptor and TNF ligand superfamilies, respectively, activate osteoclasts while interacting with T cells, synovial fibroblasts and other cytokines (e.g. IL-1, IL-17), which results in bone resorption. Osteoprotegerin (OPG) is a decoy receptor that also belongs to the TNF receptor family and inhibits RANK-RANKL interactions. There is increased RANKL production and decreased OPG production in RA. The interaction of RANKL with IL-17 is particularly important. Regarding therapy, sulfasalazine, methotrexate and biological agents, especially TNF inhibitors suppress RANKL-mediated bone resorption and thus the development of joint erosions. RANKL-RANK interaction can be directly inhibited by recombinant OPG or anti-RANKL antibody (denosumab). Among these agents, denosumab gave promising results in experiments performed in animal models of arthritis. These were followed by a phase II human RA trial, which proved that denosumab decreased MRI erosion scores in RA.]



Further articles in this publication


[Vitamin D determination: preanalytical and analytical points of view]

BHATTOA Harjit Pál




[Extraskeletal effects of parathyroid hormone]

KISS Zoltán, MUCSI István, TÚRI Sándor, SZABÓ András, KISS István, SZEBENI Andrea, KECSKEMÉTI Valéria, TÓTH Miklós, LAKATOS Péter

[The parathyroid gland and its product, parathyroid hormone (PTH) have been subjects of interests in biomedical research for 150 years. Early studies, understandably, concentrated on the primary function: the regulation of serum calcium level. In the past few decades, however, more and more data have shown that, in contrast with the classical view, PTH receptors are expressed not only on bone and kidney cells, but in almost all organs of the human body. Therefore, the effect of PTH obviously cannot be limited to the regulation of bone and mineral metabolism. Systemic symptoms of hyperparathyroidism also became more understandable and explicable by the results of studies on the extraskeletal effects of PTH. Despite the intensive research, the mechanisms of PTH-mediated effects are not well understood in a number of areas. Therefore, it is of great importance to perform further studies in this field, which will hopefully expand our knowledge soon. In our current work, we aim to summarise the nonclassical, extraskeletal effects of PTH (that is, those not related to the regulation of bone metabolism and kidney function) and the results of related studies.]


[Personal genome - brave new world?]

ÁRVAI Kristóf, KÓSA János Pál


[The relationship of coronary heart disease and bone from a different point of view: is lumbar vertebral density a positive predictor of coronary heart disease in women?]


[BACKGROUND - A number of international data demonstrate the relationship between cardiovascular disease and bone density, osteoporosis and osteopenia. It is possible that bone formation/remodeling and vascular calcification are influenced by common pathogenetic factors (adipocytokines, inflammatory processes). Our aim was to assess this relationship among Hungarian patients. PATIENTS AND METHODS - We examined 82 patients (49 men and 33 women). The patients underwent a DEXA measurement and fasting blood sampling with full metabolic profiling within one month following an elective coronarography. Coronary state was characterised by the Gensini-score. RESULTS - Femur neck T-score values showed significant decreases in the CHD+ group (patients having at least one significant coronary stenosis), compared with the CHD- group (patients with no history of significant coronary stenosis) (-0.22 vs. -0.85, p<0.05) when the two genders were examined together. In women, lumbar BMD showed a significant positive correlation (r=+0.37, p=0.03), and the levels of adiponectin and HDL-cholesterol showed significant negative correlations (r=-0.311, p=0.04, és r=-0.38, p=0.03) with the Gensini-score. Neither the HOMA-index that characterises insulin resistance, nor the majority of conventional lipid and lipoprotein risk factors showed any association with the severity of coronary heart disease. CONCLUSION - On the basis of our results, the relationships between femur and lumbar regions and coronary heart disease are opposite in nature, which is probably explained by the different regulatory mechanisms in these two regions. Adiponectin may have an important role in the regulation of this relationship, which is independent of insulin resistance.]

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Hungarian Immunology

[Early arthritis]


[Definitive autoimmune-inflammatory rheumatic diseases are often preceded by undifferentiated clinical syndromes including undifferentiated polyarthritis (UDP), undifferentiated connective tissue disease (UCTD) and early rheumatoid arthritis (RA). These are considered as distinct clinical entities. However, due to extensive overlapping patterns in clinical picture and treatment, these diseases may be commonly termed as ”early arthritis”. The optimal follow-up of such patients may only be carried out at specialized early arthritis clinics. Effective patient care should include the early use of prognostic indicators, as well as flexible pharmacological therapy.]

Hungarian Immunology

[Experience with infliximab treatment of rheumatoid arthritis in Hungary]


[We conducted the first Hungarian open-label study using infliximab (Remicade) in 62 rheumatoid arthritis (RA) patients. The mean disease duration was 8.7 years. Patients receiving methotrexate for at least 3 months with active RA were included in the study. All patients received concomittant methotrexate treatment. Results indicated a 61%, 35% and 18% improvement in ACR20, ACR50 and ACR70, respectively. In most patients, dramatic improvement was seen as soon as after the first or second infusion.]

Lege Artis Medicinae


BÉLY Miklós, APÁTHY Ágnes

[INTRODUCTION - The lethal septic infection was studied in a randomized (non-selected) autopsy population of 234 in-patients with rheumatoid arthritis. The patients died at the National Institute of Rheumatology between 1970 and 1999. PATIENTS AND METHOD - The aims of this study were to determine the prevalence of lethal septic infection with or without purulent arthritis in rheumatoid arthritis; the relationship between purulent arthritis and lethal septic infection; the clinically missed diagnosis of lethal septic infection and purulent arthritis; the influence of the main complications and associated diseases on lethal septic infection with and without purulent arthritis; the pathogens in lethal septic infection; and the clinico-laboratory parameters associated with lethal septic infection in rheumatoid arthritis. RESULTS - Lethal septic infection was found in 31 (13.24%) of 234 rheumatoid arthritis patients. Purulent arthritis complicated lethal septic infection in 15 (6.4%) of 31 patients. There was a significant association between lethal septic infection and purulent arthritis. Sepsis was detected clinically in 17 of 31 lethal cases and purulent arthritis was detected 9 of 15 septic infection complicated with suppurative articular processes. The coexistent complications (systemic vasculitis, AA amyloidosis), and associated diseases (tuberculosis with or without miliary dissemination, malignant tumors, diabetes mellitus) did not influence the prevalence of septic infection. The most frequent pathogenic agents were: Staphylococcus aureus, Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, Klebsiella species, Streptococcus species. The patients with septic infection had significantly lower levels of beta-globulin, and higher values of Waaler-Rose or latex fixation test in comparison to patients without septic infection or without complications. CONCLUSION - Lethal septic infection may exist in rheumatoid arthritis without the classical clinical symptoms of sepsis, and clinically latent suppurative processes may be found at autopsy. The missed clinical diagnosis of a fatal complication is explained by the weak immune response and atypical clinical symptoms of elderly patients mainly treated with steroids and immunosuppressive drugs.]


[New approaches to the treatment of osteoporosis]


[Osteoporosis is a significant health care problem, and its treatment is of major interest. Despite of the wide spectrum of therapeutical modalities, the effective cure for all forms of this condition has not yet been developed. For this reason, the focus is on the development of new pharmacological approaches. The RANK/RANKL/OPG system discovered one and a half decades ago provides a tool for the neutralization of the osteoclast-stimulating RANKL by the use of monoclonal antibodies. Catepsin-K inhibitors offer another pathway for the inhibition of bone degradation. Anti-sclerostin and anti-Dkk-1 antibodies may stimulate bone formation by the release of Wnt signal transduction system. Other administration methods for PTH analogs, new generations of selective estrogen receptor modulators and antibodies against vitronectin receptors as well as potential new drug targets will enable us to fight bone loss more efficiently.]


[Vitamin D receptor gene BsmI polymorphism in rheumatoid arthritis and associated osteoporosis]

PÁKOZDI Angéla és munkatársai

[Rheumatoid arthritis is frequently associated with secondary osteopenia or osteoporosis. Gene polymorphisms, such as the BsmI polymorphism of the vitamin D receptor gene are likely to be be involved in the pathogenesis of osteoporosis. However, very little information is available on the role of the BsmI polymorphism in rheumatoid arthritis or in arthritisassociated metabolic bone disorders. Here the authors review international data on vitamin D receptor gene polymorphisms and their relationship with bone metabolism.The authors emphasize that more detailed research is needed to clarify the relationship between these polymorphisms and rheumatoid arthritis.]