[Diagnosis and treatment of osteoporosis and rheumatoid arthritis in accordance with German guidelines. Results of a survey of patients, primary care physicians and rheumatologists]. / Diagnostik und Behandlung der Osteoporose bei rheumatoider Arthritis vor dem Hintergrund der Leitliniennutzung. Ergebnisse einer Befragung von Patienten, Hausärzten und Rheumatologen (ORA-Studie).

In a cross-sectional study the prevalence of osteoporosis and osteopenia in patients with rheumatoid arthritis (ORA study) was investigated. Additionally, patients, their family doctors and rheumatologists were surveyed on their awareness of osteoporosis in RA, prevention, diagnosis, treatment and use of guidelines.In the years 2005 and 2006 a total of 532 patients with RA (98 men, 434 women) aged 23-87 years were consecutively recruited from 9 German centers for rheumatology. Clinical examination included a detailed documentation of osteoporosis medication. Dual-energy X-ray absorptiometry (DXA) was used to measure bone mineral density (BMD) at the lumbar spine and neck of the femur. Questionnaires on osteoporosis were sent to 119 family doctors (87 men, 32 women) and 44 rheumatologists (30 men, 14 women).The survey showed that rheumatologists had a higher awareness of osteoporosis in RA and compared to family doctors they estimated a higher frequency and tested RA patients more often for osteoporosis. In line with osteoporosis guidelines rheumatologists and family doctors saw an indication for densitometry in RA patients on steroid therapy and/or low intensity trauma fractures. In contrast to the 2006 recommendations of osteoporosis guidelines 50% of family doctors and rheumatologists preferred bisphosphonate off-label-therapy for premeopausal women with RA and comorbid glucocorticoid-induced osteoporosis. On the other hand 50% of premenopausal RA patients with osteoporosis did not receive any osteoporosis medication.The survey revealed a high degree of guideline compliance in diagnosing osteoporosis in RA but deficits were observed in the administration of osteoporosis medication, especially in premenopausal women.

[Prophylaxis and treatment of osteoporosis in patients with rheumatoid arthritis (ORA study)]. / Medikamentöse Osteoporoseprophylaxe und -Therapie bei Patienten mit Rheumatoider Arthritis (ORA-Studie).

OBJECTIVE: The aim of this study was to examine bone mineral density (BMD), frequency of osteopenia and osteoporosis in a representative sample of patients with rheumatoid arthritis (RA) and to describe chemoprophylaxis and treatment of osteoporosis compared to evidence-based guidelines. PATIENTS AND METHODS: In 2005 and 2006, 532 patients with RA (98 men, 434 women) aged 23-87 years were recruited from 9 German rheumatology centers. Clinical examination included a detailed documentation of osteoporosis medication. Dual-energy X-ray absorptiometry (DXA) was used to measure BMD at the lumbar spine and femoral neck. Osteopenia and osteoporosis were defined according to the criteria of the World Health Organization. RESULTS: Of the RA patients 29% had normal BMD at the spine and femoral neck, 49% of the patients had osteopenia and 22% met the criteria for osteoporosis at any site. Of the patients 60% were receiving medication for prophylaxis or therapy of osteoporosis, 38% calcium/vitamin D alone, 20% as combinations mostly of calcium/vitamin D + bisphosphonate, 1% received bisphosphonate only and 1% hormone replacement therapy. Although the frequency of osteoporosis showed no significant differences between male and female patients, women with RA used osteoporosis medication more often than men (63% versus 49%, χ²-test, p <0.05). A total of 101 RA patients (83 menopausal women, 6 premenopausal women, 12 men) received corticosteroids in a daily dose of 7.5 mg or less for at least 3 months and had DXA T-scores below -2.0 at any site. In this patient group 41% of the menopausal women, 17% of the premenopausal women and 42% of the male patients were reported to receive medication with calcium/vitamin D + bisphosphonate. Calcium/vitamin D was used by 35% of the menopausal women, none of the premenopausal women and 50% of the male patients and 18% of the menopausal women, 67% of the premenopausal women and 8% of men received no prophylaxis or treatment for osteoporosis. CONCLUSION: According to the DVO (German Society for Osteoporosis) guidelines for osteoporosis (2009) menopausal women with corticosteroid therapy < 7.5 mg per day for at least 3 months and DXA T-scores below -2.0 should receive treatment with bisphosphonate and calcium/vitamin D. The data show that there were still deficits concerning prophylaxis and treatment of osteoporosis in RA.

Immunopathogenesis of rheumatic diseases in the context of neuroendocrine interactions.

Growing evidence supports the hypothesis that alterations of the stress response and interactions between the neuroendocrine and immune systems contribute to the pathogenesis of rheumatic diseases such as rheumatoid arthritis (RA). In particular, the hypothalamus-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS) are of special interest. Polymorphisms of the corticotropin-releasing hormone (CRH)-regulating region have been described recently. These polymorphisms are differentially distributed in RA patients and healthy subjects of various ethnic origin, thus supporting the hypothesis that they represent a new genetic marker for RA susceptibility. The decreased expression of beta(2)-adrenergic receptors (beta(2)-R) on lymphatic cells in rheumatic diseases like RA, together with an impaired influence of catecholamines on immune function in these patients, further underlines the concept of a dysfunction of the ANS in rheumatic diseases. Results from work in this field will provide more insight into the pathogenesis of RA and help to establish novel therapies for this chronic rheumatic disease.

A comparison of prednisolone with azathioprine and prednisolone with intramuscular gold in rheumatoid arthritis.

Pulse prednisolone hemisuccinate therapy (500 mg given intravenously on three occasions over two weeks) has been combined with either intramuscular sodium aurothiomalate or azathioprine in an assessment of 30 patients with rheumatoid arthritis. Significant improvement in a variety of clinical and biochemical assessments was seen in both groups. Both treatments were well tolerated by the patients and prednisolone appeared to accelerate the response to sodium aurothiomalate and azathioprine but there was no great evidence that it enhanced it.

Antibodies against cyclic citrullinated peptide are associated with the DRB1 shared epitope and predict joint erosion in rheumatoid arthritis.

OBJECTIVE: To evaluate antibodies against cyclic citrullinated peptide (anti-CCP antibodies) for their predictive value for severe joint destruction in rheumatoid arthritis (RA) and to examine their relationship to shared epitope (SE)-positive DRB1 alleles. METHODS: Concentrations of anti-CCP antibodies were determined in sera from 126 patients with recent onset RA who had been followed prospectively for 6 yr. Progression of joint destruction was evaluated according to Larsen by scoring radiographs from the hand and feet taken at baseline and after 1, 2, 4 and 6 yr of observation. In addition to clinical parameters, the presence of SE-positive DRB1 alleles and of rheumatoid factor IgM and IgA was determined. RESULTS: Anti-CCP antibodies were found more frequently and in higher concentrations in both DRB1*01-positive and in DRB1*04-positive SE-positive patients compared with SE-negative patients. Severe joint destruction as defined by a Larsen score in the upper third of the study population was predicted by positivity for anti-CCP antibodies, by the presence of SE-positive DRB1*04 alleles and by the presence of erosive disease at initial presentation. Multiple logistic regression analysis revealed that SE-positive DRB1*04 alleles and anti-CCP antibodies exerted a significant influence on the progression of joint destruction. CONCLUSION: The association of anti-CCP antibodies with DRB1*01 and with SE-positive DRB1*04 alleles implies a functional role for the SE sequence motif. The determination of SE-positive DRB1*04 alleles and of anti-CCP antibody positivity facilitates the prediction of disease course and prognosis at the time of initial presentation.

The TNF superfamily member LIGHT contributes to survival and activation of synovial fibroblasts in rheumatoid arthritis.

OBJECTIVES: The TNF superfamily member LIGHT has a T-cell co-stimulatory role and has previously been associated with inflammation and autoimmunity. To investigate its role in rheumatoid arthritis (RA), a disease where activated T cells contribute in a prominent way, we have analysed the expression of LIGHT and its receptors in RA and analysed its effects on synovial fibroblasts in vitro. METHODS: The expression of LIGHT was measured in synovial tissues and fluids and the receptors of LIGHT were detected on synovial fibroblasts derived from patients with RA and osteoarthritis (OA). The effects of recombinant LIGHT on the production of proinflammatory cytokines and proteases and on the apoptosis of synovial fibroblasts was assessed. RESULTS: LIGHT mRNA was present in synovial tissues of patients with RA but not with OA. Correspondingly, soluble LIGHT protein could be detected in RA synovial fluid samples at much higher levels than in synovial fluid from patients with OA. Immunohistochemical detection of LIGHT and analysis of synovial fluid cells by flow cytometry revealed CD4 T cells as the major source of LIGHT in the rheumatoid joint. Synovial fibroblasts from RA patients were found to express the LIGHT receptors HVEM and LTbetaR. Recombinant LIGHT induced RA synovial fibroblasts to upregulate MMP-9 mRNA, CD54 and IL-6 in an NF-kappaB-dependent fashion. In vitro, exposure of cultured synovial fibroblasts to LIGHT reduced FAS-mediated apoptosis significantly, without affecting the rate of spontaneous apoptosis. CONCLUSIONS: The results provide evidence for a novel T-cell-dependent activation of synovial fibroblasts by LIGHT in joints of patients with RA, contributing to an inflammatory and destructive phenotype.

[Rheumatoid arthritis and cardiovascular complications]. / Rheumatoide Arthritis und kardiovaskuläre Komplikationen.

Rheumatoid arthritis is associated with increased morbidity and mortality due to cardiovascular events. Elevated concentrations of acute-phase proteins and cytokines and endothelial dysfunction, demonstrated also by lack of traditional risk factors, play an important role in these complications. Antirheumatic drug treatment can modify the frequency and severity of cardiovascular events.

Promoter polymorphisms regulating corticotrophin-releasing hormone transcription in vitro.

To investigate whether polymorphisms in the corticotrophin-releasing hormone (CRH) promoter are associated with altered CRH gene regulation, we studied the reactivity of three recently described promoter variants in vitro. The 3625 bp variants A1B1, A2B1 and A2B2 of the human CRH promoter were cloned in the 5' region to a luciferase reporter gene and transiently transfected into both mouse anterior pituitary cells AtT-20D16vF2 and pheochromocytoma cells PC12. Incubation with 8-Br-cAMP alone or in combination with cytokines significantly enhanced the promoter activity in both cell lines studied by up to 22-fold. However, dexamethasone antagonised cAMP effects on CRH expression in AtT-20 cells while showing no effect on PC12 cells, indicating that tissue-specific factors play a crucial role. Among the haplotypes studied, A1B1 exhibited the greatest reactivity on various stimuli. Electric mobility shift assay (EMSA) was performed to study whether the described polymorphic nucleotide sequences in the 5' region of the hCRH gene interfere with binding of nuclear proteins. A specific DNA protein complex was detected at position -2353 bp for the wild type sequence only, possibly interfering with a binding site for the activating transcription factor 6 (ATF6). Taken together, this is the first study to demonstrate that CRH promoter reactivity varies between the compound promoter alleles.

[T cell-dependent monocyte activation, TNFalpha and apolipoprotein A-I in autoimmunity and inflammation]. / T-Zell-abhängige Monozytenaktivierung, TNFalpha und Apolipoprotein A-I in Autoimmunität und Inflammation.

Rheumatoid arthritis is characterized by a massive overproduction of monokines like TNFalpha, IL-6 and IL-1beta, which are predominantly produced by monocytes and macrophages. To date, the exact mechanisms of monocyte/macrophage activation have not been fully elucidated. One possible mechanism is their cell contact-dependent activation by activated T cells. The direct cell contact of monocytes/macrophages and T cells leads to an increased production of pro-inflammatory cytokines such as TNFalpha and IL-1beta. Stringent control of this mechanism by inhibitory factors appears mandatory under physiological conditions in order to avoid systemic cytokine release syndromes. The presence of inhibitory factors in the serum could represent such a mechanism. In healthy donors, apolipoprotein A-I was identified as such an inhibitory serum protein. In patients with rheumatoid arthritis, apolipoprotein A-I is found in decreased concentrations, possibly due to its role as a negative acute phase protein. The role of this and other inhibitory serum molecules are discussed.

[Cardiovascular manifestations in rheumatoid arthritis]. / Kardiovaskuläre Manifestationen bei Rheumatoider Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by a polyarticular joint inflammation which eventually leads to joint destruction and general disability. Besides these polyarticular manifestations, several systemic immune phenomena have been described. An increased mortality in RA patients is evident and is mainly caused by an increased cardiovascular risk. The correlation between disease activity and mortality highlighted the important role of the systemic inflammatory reaction in induction and progression of vascular damaging processes. Endothelial dysfunction and vascular inflammation are important, mechanisms in atherosclerosis and induced by conventional risk factors and systemic inflammation. It has been shown that the deleterious influence of conventional risk factors is aggravated by inflammatory mediators, mainly by pro-inflammatory cytokines. In addition, certain inflammatory mediators exert damaging effects to blood vessels. Especially CRP, merely considered as a risk indicating parameter in the past, has attracted remarkable attention. Also certain RA specific immune phenomena are of considerable proatherosclerotic potential. At least in part, they could be responsible for the excess mortality in RA patients. The newer TNFalpha blocking agents interfere with different mechanisms responsible for induction and perpetuation of atherosclerotic processes. Time will show whether they make a remarkable impact on the cardiovascular mortality in RA patients.

[Significance of synovial diagnosis]. / Stellenwert der Synoviadiagnostik.

Judging the value of synovia diagnosis we issue from the points of view of diagnostics, degree of severity of the arthritic syndrome and the assessment of the success of therapy. With the help of the results of own examinations of 768 joint punctates as well as the sera belonging to them practical conclusions are drawn and the essential signs for the synovia diagnosis established by factor analysis are reported.

[A new acute-phase protein. II. Quantitative determination in the serum of patients with rheumatoid arthritis]. / Untersuchungen über ein neues akute-Phase-Protein. II. Quantitative Bestimmung im Serum von Patienten mit Rheumatoid-Arthritis.

An antigen (SF1 or TSGA) originally found in the inflammable synovial fluid of man, which comes from the cytoplasm of neutrophils, possesses the properties of an acute-phase-protein. The production of a specific antiserum against this antigen and the method of its quantitative determination by means of the Mancini-technique are described. In 89 sera of patients with rheumatoid arthritis the antigen was determined. First results of this investigation which speak for a dependence of the antigen concentration in the serum on activity and progression of the disease are reported.

[Leukocyte agglomeration in synovial fluid]. / Leukozytenagglomeration im synovialen Milieu.

The agglomeration of leucocytes serves as evidence of leucocytic activation. In rheumatoid arthritis it can be used as a very sensitive criterion of activity. Patients with rheumatoid arthritis with joint effusions showed a high agglomeration of leucocytes in 97%, i.e. a clear activation of leucocytes. In 74.3% the number of punctate leucocyte agglomerated increased. Punctates with a proof of a spontaneous agglomeration of leucocytes showed the most intensive inclination to agglomeration also after incubation. By synovial fluid normal but also leucergic granulocytes could be stimulated to increased agglomeration to leucocytes. In the synovial fluid also factors stimulating the agglomeration of leucocytes are found. They probably come from punctate granulocytes and stimulate also the chemotaxis and activation of the blood granulocytes. Since granulocytes essentially participate in the inflammatory reaction of the rheumatoid arthritis and in the joint destruction evoked by it, the therapeutic aspect should be directed also to the inhibition of such leucocyte-activating factors in the synovia.

[Determination of lymphocyte subpopulations and their activation status in patients with rheumatoid arthritis treated with plasma exchange and pulse therapy]. / Bestimmung von Lymphozytensubpopulationen und ihres Aktivierungsstadiums bei Patienten mit Rheumatoid-Arthritis unter Plasmaaustausch und Puls-Therapie.

In patients with systemic rheumatoid arthritis (RA) and extraarticular manifestation treated with plasma exchange or prednisolute-pulse-therapy, respectively, and followed by an additional immunosuppression by cyclophosphamide we have assessed the lymphocyte subpopulations of the peripheral blood and the cells expressing activating markers by means of monoclonal antibodies using fluorescence microscopy or fluorescence flow cytometry. Before therapy the patients showed a very different level of lymphocyte subpopulations tested. During treatment in both groups of patients there was not any uniform tendency in CD3, CD4 and CD8 positive cells. The percentage of activated lymphocytes was initially elevated and we found significant reduction, mainly in the 4th week after starting of therapy. Following in the most cases the level recovered to the state before therapy. For the single patients an individual pattern of reaction was evident in relation to the initial position before treatment.

[Differential-diagnostic and prognostic significance of antinuclear factors]. / Differentialdiagnostische und prognostische Bedeutung antinukleärer Faktoren

On the patients of the consulting point for rheumatic diseases of the policlinical institute of the Karl-Marx-University Leipzig analytic examinations of the course for the existence of the LE-cell factor were carried out. We used the loose-body-test after van Soeren as screening test, controlled positive test results for several times under the same experimental conditions and supplemented it by the LE-cell test after Zinkham and Conley or later on by the immune fluorescence test. All patients with positive proof of LE-cells were examined for reference signs concerning a visceral lupus erythematodes, in which cases at the beginning of the examination nobody fulfilled the criteria of the diagnosis of a visceral lupus erythematodes. We tested the constancy of the proof of the LE-cells as well as the diagnosis in the course of longer periods. Typical changes of a visceral lupus erythematodes were seen only rarely. In 2 patients the joint processes were concomitant symptoms of a chronic aggressive hepatitis. In the p.c.p. at stage II to IV with positive LE-cell factors in the first place must be thought of a proof of LE-cell factors induced by drugs. In these cases gold is of practical importance. We could confirm that in contrast to the typical active visceral lupus erythematodes in p.c.p. the antinuclear factors have only a weakly positive result and are above all inconstant.

[Clinical assessment of the activity and results of therapy in joint diseases through cytologic examination of puncture fluids (author's transl)]. / Zytologische Aktivitäts- und Therapieerfolgsbeurteilung an Gelenkpunktaten aus klinischer Sicht.

Activity and results of therapy of joint diseases can be evaluated by means of cytological examinations of the synovia which is at the same time a prerequisite for differential diagnosis using the puncture fluid. Our cytological examinations of more than 700 puncture fluids stemming from different joint diseases were carried out immediately after the puncture on the fresh material, in order to prevent misinterpretation. This may occur through flaking out in stored material, which results in decrease in the cell count and a non-representative differential cell picture in the supernatant, as well as through degeneration of cells. In two thirds of our patients the local process activity, measured in terms of the cytological phase of activity, became evident in the total clinical activity. The synovia analysis furthermore permits objective assessment of the result of intra-articular injection treatment. Intractable activity, substantiated through synovia examination indicates synovectomy.

[Synovial milieu in gouty arthritis]. / Synoviales Milieu bei Arthritis urica.

The synovial milieu in uric arthritis is characterized with the help of own findings of examinations and data in literature. Apart from the mean values of cytological and biochemical findings of the synovia the changes under therapy are described on the basis of individual examples. The formation of monosodium urate crystals seems to be the starting point of the inflammatory joint process in gout. The size of the arthritic syndrome is among others determined by the local metabolic process, in which case lactate acidosis and reduction of energy as well as the increase of enzyme activities seem to stand in the foreground.

[Extra-intestinal Manifestations of chronic inflammatory Bowel diseases]. / Extraintestinale Manifestationen chronisch-entzündlicher Darmerkrankungen.

Approximately one third of all patients with Crohn's disease and ulcerative colitis suffer from extra-intestinal manifestations of their inflammatory bowel disease. Most commonly those symptoms occur simultaneously with the CED symptoms; they can, however, either precede them or appear later on in the course of the disease. The most frequent extra-intestinal symptoms are arthralgias of peripheral joints and spine, which are usually bland and self-limiting, while ankylosing spondylitis and erosive arthritides are rare. Skin lesion and eye affections can also parallel the bowel condition, but occasionally they precede intestinal manifestations and can be a first diagnostic clue. In addition, different extra-intestinal symptoms tend to simultaneously co-occur more frequently in some patients with CED, while others are not affected at all. Immunogenetic parameters play a role for the manifestations of the pathologic immune response both in the gut and in the musculo-skeletal systems, as indicated by associations with MHC class I alleles. Enteropathic microorganisms are also thought to be involved in the pathogenetic mechanisms.

Detection of immunoglobulin G glycosylation changes in patients with rheumatoid arthritis by means of isoelectric focusing and lectin-affinoblotting.

Patients with rheumatoid arthritis have a reduced prevalence of immunoglobulin G (IgG) oligosaccharide chains terminating in galactose, thus exposing N-acetylglucosamine. We analyzed IgG glycosylation in patients with rheumatoid arthritis, patients with early synovitis, and in controls by means of isoelectric focusing and lectin-affinoblotting. The ratio of N-terminal N-acetylglucosamine and galactose was determined using specific biotin-labeled lectins. The IgG glycosylation state may well be of clinical value in the differential diagnosis of patients presenting with early synovitis.

[Functional diagnostics of the adrenal cortex following long term treatment with prednisolone]. / Zur Funktionsdiagnostik der Nebennierenrinde nach Prednisolonlangzeittherapie.

Promounced cases of disturbances of the function of the adrenal cortex may more certainly be found out with the help of the enlarged sinacthen test than after a stimulation done only but once. In a long-term prednisolone therapy of 10 mg/a day we could observe signs of disturbances of the function of the adrenal cortex. A clear evidence in the estimation of the individual value is possible only in decreased plasmacortisol levels which are during the whole course of the experiment. When a prednisolone therapy is established for a longer time apart from the sequels at the adrenal cortex should be thought also of the great number of the side effects caused by the catabolic properties of the cortico-steroids.