[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.

[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.

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.

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.

[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.

[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.

[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.

[Internist's therapy of rheumatoid arthritis]. / Internistische Therapie der rheumatoiden Arthritis.

Rheumatoid arthritis is the most common inflammatory joint disease and is characterized by chronic, symmetric, erosive synovitis of small joints of hands and feet. Prevalence in women is threefold higher than in man. Structural damage of the joints starts between the first and second year of the disease. Early therapeutic interventions can alter the course of rheumatoid arthritis by delaying the progression of radiographic joint destruction, which correlates with the grade of disability. Approval of new biologic antirheumatic drugs in the last few years improved the outcome of rheumatoid arthritis.

Prospective analysis of the impact of HLA-DR and -DQ on joint destruction in recent-onset rheumatoid arthritis.

OBJECTIVE: To evaluate the differential impact of HLA-DR and -DQ on the progression of erosive disease in the clinical course of early rheumatoid arthritis (RA). METHODS: HLA genotyping for HLA-DR and -DQ was carried out in a prospective study of 87 patients with early RA. The progression of erosive disease was assessed by radiological scores over a period of 2 yr in all patients and over 4 yr in 77 patients. The impact of HLA markers was evaluated by univariate comparisons and by multiple logistic regression analyses. RESULTS: Patients expressing the RA-associated shared epitope (SE) on a DRB1*01-positive or, most prominently, on a DRB1*04-positive allele had higher Larsen scores at all time-points analysed when compared with SE-negative patients. A similar impact on radiological progression was seen for the RA-predisposing DQ3, but not for DQ5 heterodimers. In the presence or absence of the DRB1 SE, no additional effects could be discerned for RA-associated DQ molecules. The presence of a DERAA-positive DRB1 allele was associated with a slower pace of joint destruction. While gene dosage effects were seen for SE compound homozygosity, no effect for DQ3 homozygosity could be discerned. CONCLUSION: Although a significant influence of HLA-DQ3 heterodimers on the progression of erosive joint destruction was seen, the analysis of the HLA-DQ locus did not add additional information over the study of HLA-DR including the determination of the SE and the DERAA motif in order to predict the development of severe progressive joint destruction.

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.

[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.

Immunogenetic markers and seropositivity predict radiological progression in early rheumatoid arthritis independent of disease activity.

OBJECTIVE: A prospective clinical study of patients with recent onset rheumatoid arthritis (RA) to examine the relationship between inflammatory disease activity and joint destruction in a 4 year followup, and to evaluate prognostic markers for severe joint erosions early in the disease. METHODS: Eighty-seven patients with RA according to the American College of Rheumatology criteria and a disease duration < 2 years were followed for an observation time of 2 to 4 years (mean 3.1 yrs). Variables of clinical and laboratory disease activity were monitored, and HLA-DRB1 alleles were determined. Hand and foot radiographs were taken every 6 months. RESULTS: Multivariate analysis of independent contributions of covariates to progression of joint destruction resulted in a mixed effect regression model with significant influences for the presence of a shared epitope (SE) positive DR4 allele (SE+ DR4+; p = 0.007), rheumatoid factor (RF) IgA (p = 0.01), and sex (p = 0.059), but not for clinical variables or acute phase reactants. The odds ratio to reach a Larsen score above 32 during the observation period of 4 years was increased in patients positive for RF IgM (OR 2.7, p = 0.019), for the shared epitope on a DR4 allele (OR 8.6, p < 0.005), and in patients with erosions already at study entry (OR 11.9, p = 0.001). The highest sensitivity and specificity for the prediction of severe bone destruction (84% and 79%) were found when the presence of either a SE+ DR4 allele or of early erosions was used as a prognostic marker (OR 20.4, p < 0.0001). CONCLUSION: Our results show the pace of joint destruction in RA to be influenced by the presence of SE+ DR4 alleles, RF production, and sex and by the presence of erosive disease at presentation. Those prognostic markers exert their influence independently from the inflammatory disease activity.

Regulation of beta2-adrenergic receptors on CD4 and CD8 positive lymphocytes by cytokines in vitro.

Increasing evidence points to a close relationship between the autonomic nervous system and the immune system. To further investigate mechanisms regulating beta2-adrenergic receptor (beta2R) expression in lymphocytes, the influence of cytokines on the density of beta2R on purified CD4+ and CD8+ lymphocytes was determined in vitro. beta2R were determined by means of a radioligand binding assay with (125I)iodocyanopindolol. CD4+ and CD8+ lymphocytes were incubated with catecholamines, interleukin 1beta (IL-1beta) and interleukin 2 (IL-2) for 6-72 h. The results demonstrate declining beta2R numbers on CD4+ and CD8+ lymphocytes in vitro augmented by epinephrine. IL-1beta has no effect on beta2R expression compared to medium. However, incubation with IL-2 resulted in an up-regulation of beta2R on CD8+ lymphocytes. Thus, the study demonstrates a differential regulation of beta2R on T-lymphocyte subpopulations with CD8+ lymphocytes being more susceptible to mechanisms of beta2R modulation than CD4+ lymphocytes. The findings further strengthen the concept of a close interplay between the autonomic nervous system and the immune system.

[Guideline for the joint swelling symptom--primary physician problem management and referral indications. German Society of Rheumatology "Quality Assurance" Committee]. / Leitlinie für das Symptom Gelenkschwellung--Primärärztliches Problemmanagement und Uberweisungsindikationen. Deutsche Gesellschaft für Rheumatologie Kommission "Qualitätssicherung".

The guideline "Joint Swelling" is addressed to primary care physicians--general practitioners, internists or orthopedists without special experience in rheumatology. It provides a framework for interviewing patients, as well as for physical, laboratory and imaging examinations and for selection of treatment appropriate to the level of primary care. Situations which call for urgent evaluation and criteria for referral to rheumatologists are described. The appendix contains comments on signs and symptoms to differentiate arthralgia from joint swelling and on the diagnostic value of a history of joint swelling without confirmation by the physician. Further recommendations for the evaluation of patient history and physical and technical examinations are given in a tabular form. The significance of laboratory and imaging procedures is discussed.