2015 Recommendations for the management of polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative

Therapy for polymyalgia rheumatica (PMR) varies widely in clinical practice as international recommendations for PMR treatment are not currently available. In this paper, we report the 2015 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) recommendations for the management of PMR. We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology as a framework for the project. Accordingly, the direction and strength of the recommendations are based on the quality of evidence, the balance between desirable and undesirable effects, patients' and clinicians' values and preferences, and resource use. Eight overarching principles and nine specific recommendations were developed covering several aspects of PMR, including basic and follow-up investigations of patients under treatment, risk factor assessment, medical access for patients and specialist referral, treatment strategies such as initial glucocorticoid (GC) doses and subsequent tapering regimens, use of intramuscular GCs and disease modifying anti-rheumatic drugs (DMARDs), as well as the roles of non-steroidal anti-rheumatic drugs and non-pharmacological interventions. These recommendations will inform primary, secondary and tertiary care physicians about an international consensus on the management of PMR. These recommendations should serve to inform clinicians about best practices in the care of patients with PMR.(AU)

[Expectations of rheumatologists on imaging results]. / Erwartungen des Rheumatologen an die Bildgebung.

CLINICAL/METHODICAL ISSUE: Clinical examination and laboratory results are often insufficient to support therapeutic decisions. STANDARD RADIOLOGICAL METHODS: Diagnosis and organ-related imaging may provide important additional information for initial diagnosis (differential diagnoses), follow-up and prognosis. Especially functional imaging techniques, such as ultrasound and magnetic resonance imaging are becoming more and more important for early diagnosis. METHODICAL INNOVATIONS: Imaging is already recognized in the classification criteria of several rheumatic diseases and new criteria for spondyloarthritis and polymyalgia rheumatica aim more and more at early diagnosis using functional imaging techniques, such as ultrasound and magnetic resonance imaging. PERFORMANCE: Specific imaging findings are helpful for eliminating differential diagnoses. During follow-up disease control the status as well as progression of structural damage can be documented. In selected diseases imaging allows prognostic statements on both disease progression and therapeutic response to specific medication. ACHIEVEMENTS: The evidential value of imaging results varies with the rheumatological expectations. PRACTICAL RECOMMENDATIONS: Overall rheumatological expectations on imaging differ widely and therefore support a differentiated use of imaging techniques.

Urate oxidase (rasburicase) for treatment of severe acute gout: a case report.

A 73-year-old female patient was referred to our department because of gouty arthritis in the right first toe. The patient suffered from progressive renal failure because of pauci-immune necrotising glomerulonephritis. As severe hyperuricaemia would further worsen progredient renal insufficiency and therapy with allopurinol was contraindicated because of renal insufficiency and previous pancytopenia, the patient was treated twice with intravenous rasburicase. This therapy was well tolerated by the patient and led to the decrease of serum uric acid below the detection limit within 24 hours.

[Current therapeutic options for giant cell arteritis]. / Aktuelle Therapieansätze bei Riesenzellarteriitis.

Giant cell arteritis is the most common systemic vasculitis and affects large and medium-sized vessels. Glucocorticoids are the current standard in the therapy of giant cell arteritis. To reduce the glucocorticoid dose the European League Against Rheumatism (EULAR) suggests the addition of disease-modifying antirheumatic drugs. Of these, methotrexate represents the best investigated drug; possible alternatives include azathioprine, tumor necrosis factor-alpha inhibitors and cyclophosphamide.

[Polymyalgia rheumatica]. / Polymyalgia rheumatica.

Polymyalgia rheumatica (PMR) is a common chronic inflammatory rheumatic disease with unknown aetiology, affecting predominately people of middle age and older. Besides clinical symptoms and diagnostics, imaging techniques including sonography and magnetic resonance imaging may provide evidence of typical inflammatory lesions with bilateral bursitis subdeltoidea or subacromialis, tenosynovitis of the biceps tendon sheath and/or synovitis of the shoulder joints and thus may support the diagnosis of this disease in difficult cases. Corticosteroids are the cornerstone of treatment of PMR, but adverse events because of chronic corticosteroid use are observed in more than 50% of treated patients. Whether immunosuppressants, such as methotrexate and tumour necrosis factor-alpha inhibitors are effective in the therapy of PMR has still not yet been clarified.

Diagnostic values of history and clinical examination to predict ultrasound signs of chronic and acute enthesitis.

OBJECTIVE: To examine the diagnostic values of history of chronic enthesitic pain and clinical signs of acutely inflamed entheses to predict ultrasound (US) signs of enthesitis. METHODS: Cohort study of 21 consecutive rheumatic out-patients (female/male 18/3) with suspected multiple enthesitis and 12 controls (female/male 10/2). 429 enthesal sites according to the Maastricht Ankylosing Spondylitis Entheses Score (MASES) were evaluated by history, clinical examination, B-mode and power Doppler US. Sensitivity and specificity of history suggesting chronic enthesitic pain and clinical examination suggesting acute enthesitis were calculated using corresponding US findings as reference standard. RESULTS: Diagnostic accuracy widely varied between different MASES sites. Sensitivity and specificity of selected MASES points were 66.7 - 86.4% and 85.0 - 91.7% for history and 71.4 - 87.0% and 47.4 - 75.0% for clinical examination, respectively (p<0.05 for each). CONCLUSION: At specific enthesal sites, history of chronic enthesitic pain and clinical signs of acute inflammation are sensitive and specific for the diagnosis of chronic and/or acute inflammation.

[Diagnosis and therapy of neurological manifestations of inflammatory rheumatic diseases]. / Diagnose und Therapie neurologischer Manifestationen bei entzündlich-rheumatischen Erkrankungen.

Patients with inflammatory rheumatic diseases frequently report symptoms that may indicate an involvement of central and peripheral nervous system in addition to the known musculoskeletal symptoms. The possible symptoms can be as varied as the disease mechanism which causes them. Early correct diagnosis, adequate therapy and regular monitoring of these patients are necessary to prevent permanent disability. This article summarizes current literature on the diagnosis and therapy of neurological manifestations of inflammatory rheumatic diseases including systemic Lupus erythematodes, Behçet's disease, Sjögren's syndrome, systemic vasculitides and sarcoidosis.

Biologicals in rheumatology: Austrian experiences from a rheumatic outpatient clinic.

The efficacy of biological agents has been shown in several randomized clinical trials. However, little is known regarding the performance of these drugs in daily rheumatological care. Totally, 173 patients treated with biological agents (infliximab, etanercept, adalimumab, anakinra) were retrospectively analyzed between November 2001 and December 2005 at an Austrian rheumatic outpatient clinic. In total, 224 courses of treatment with biological agents were followed up. Among the 93 drug discontinuations observed, the most frequent causes were inefficacy (56.5%) and side effects (31.9%). In 74 patients (51%), the first biological agent was withdrawn after a median treatment period of 10.7 (range 0-80) months. A second biological agent was given to 36 patients, a third to 11 and a fourth to 3 patients. Our data underline the necessity of large observational studies to assess the full spectrum of patients treated with biological agents in clinical routine.

Clinical and functional characterisation of a novel TNFRSF1A c.605T>A/V173D cleavage site mutation associated with tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), cardiovascular complications and excellent response to etanercept treatment.

OBJECTIVES: To study the clinical outcome, treatment response, T-cell subsets and functional consequences of a novel tumour necrosis factor (TNF) receptor type 1 (TNFRSF1A) mutation affecting the receptor cleavage site. METHODS: Patients with symptoms suggestive of tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and 22 healthy controls (HC) were screened for mutations in the TNFRSF1A gene. Soluble TNFRSF1A and inflammatory cytokines were measured by ELISAs. TNFRSF1A shedding was examined by stimulation of peripheral blood mononuclear cells (PBMCs) with phorbol 12-myristate 13-acetate followed by flow cytometric analysis (FACS). Apoptosis of PBMCs was studied by stimulation with TNFalpha in the presence of cycloheximide and annexin V staining. T cell phenotypes were monitored by FACS. RESULTS: TNFRSF1A sequencing disclosed a novel V173D/p.Val202Asp substitution encoded by exon 6 in one family, the c.194-14G>A splice variant in another and the R92Q/p.Arg121Gln substitution in two families. Cardiovascular complications (lethal heart attack and peripheral arterial thrombosis) developed in two V173D patients. Subsequent etanercept treatment of the V173D carriers was highly effective over an 18-month follow-up period. Serum TNFRSF1A levels did not differ between TRAPS patients and HC, while TNFRSF1A cleavage from monocytes was significantly reduced in V173D and R92Q patients. TNFalpha-induced apoptosis of PBMCs and T-cell senescence were comparable between V173D patients and HC. CONCLUSIONS: The TNFRSF1A V173D cleavage site mutation may be associated with an increased risk for cardiovascular complications and shows a strong response to etanercept. T-cell senescence does not seem to have a pathogenetic role in affected patients.

Lack of microbial DNA in tissue specimens of patients with abdominal aortic aneurysms and positive Chlamydiales serology.

In a case-control study that included a total of 98 patients and 83 controls, the possible link between various pathogens and abdominal aortic aneurysms was investigated. For 68 patients with abdominal aortic aneurysm and age-matched controls, no differences were detected in the levels of immunoglobulin (Ig)A and IgG Chlamydiaceae and Chlamydophila pneumoniae antibodies. Patients with IgA titers positive for Chlamydophila pneumoniae showed progressive disease (defined as an annual increase of the aneurysm diameter of > or = 0.5 cm) more frequently than patients with negative IgA titers (p = 0.046). Polymerase chain reactions performed to detect DNA for Chlamydophila pneumoniae, Chlamydia trachomatis, Chlamydophila psittaci, human cytomegalovirus, Borrelia burgdorferi and Helicobacter pylori in tissue specimens of 30 patients and 15 controls were negative. In summary, Chlamydophila pneumoniae may contribute to aortic aneurysm disease progression, but DNA of this and other pathogens was not found in patients' specimens.

Use of the European preliminary criteria, the Breiman-classification tree and the American-European criteria for diagnosis of primary Sjögren's Syndrome in daily practice: a retrospective analysis.

This study was conducted to assess the use of the European preliminary criteria, the Breiman-classification tree and the American-European criteria for diagnosis of primary Sjögren's Syndrome (pSS) in daily practice. A retrospective analysis of 17 consecutive patients with pSS (European criteria) was performed evaluating the application of the Schirmer test, semiquantitative sialoscintigraphy, immunologic tests, including rheumatoid factor, antinuclear antibodies, Sjögren's syndrome autoantibodies (SS-A, SS-B) and lip biopsy. Out of the 17 patients with pSS according to the European criteria, 15 patients fulfilled the classification tree (=88.2%), and 4 patients fulfilled the American-European criteria (=23.5%, P = 0.001). In the four patients fulfilling the American-European criteria, a positive result of the sialoscintigraphy was not crucial for the diagnosis according to these criteria. In conclusion, the American-European criteria are more stringent than the European preliminary criteria. We assume the role of sialoscintigraphy to be reduced when applying the American-European criteria.

[Sonography of synovial and erosive inflammatory changes]. / Sonographie synovialer und erosiver entzündlicher Veränderungen.

High-frequency sonography enables excellent detection of early erosions and synovial proliferations. Power Doppler sonography (PDUS) allows for an improved characterization of articular and peritendinous augmented volume, because detection of hypervascularity correlates with inflammatory activity and further is helpful in differentiation from effusion and inactive pannus. The use of contrast media improves the sensitivity of vascularity detection, because they allow for a delineation of vessels at the microvascular level. This is of increased interest, as the development of new therapeutic options targeting the microvascular level calls for earlier diagnosis and optimal assessment of disease activity. Because of good availability, cost effectiveness, and patient acceptance, sonography facilitates early diagnosis of synovial proliferations and erosions as well as therapy follow-up.

High positive predictive value of specific antibodies cross-reacting with a 28-kDa Drosophila antigen for diagnosis of ankylosing spondylitis.

OBJECTIVES: Diagnosis of ankylosing spondylitis (AS) can be difficult, and a specific laboratory test has not yet been introduced as a routine diagnostic tool. Our aim was to evaluate the diagnostic value of antibodies specifically binding to a recombinant 28-kDa antigen for the diagnosis of AS. METHODS: Blinded sera were tested for antibodies binding to the procaryotically expressed 28-kDa protein using an enzyme-linked immunosorbent assay (ELISA). This purified 28-kDa protein is produced by a specific clone from an embryonic Drosophila hydei Xgtl I c-DNA library and is bound by human antibodies cross-reacting with both a 36-kDa protein of chromosomes from Drosophila melanogaster and a 69-Da HeLa S3 protein potentially involved in signal transduction pathways. RESULTS: Serum concentrations of antibodies cross-reacting with this specific antigen were increased in 371 patients with AS compared with 37 healthy controls (39.5 vs 22.6 U/ml; P = 0.004). The positive predictive values of this ELISA test for AS were between 95.1% (95% confidence interval 90.6-97.9%) for a cut-off level of 50 U/ml and 97.4% (92.7-99.5%) for a cut-off level of 75 U/ml, and the sensitivities were between 42.1% (37.0-47.3%) for a cut-off level of 50 U/ml and 30.7% (26.1-35.7%) for a cut-off level of 75 U/ml. CONCLUSIONS: Serum ELISA tests for antibodies cross-reacting with the 28-kDa antigen show a high positive predictive value for AS of more than 95%.

Preferential type 1 chemokine receptors and cytokine production of CD28- T cells in ankylosing spondylitis.

OBJECTIVE: To examine serum levels of type 1 and type 2 chemokines and lymphocytic expression of chemokine receptors, and to compare the results with lymphocytic cytokine production in patients with ankylosing spondylitis (AS). METHODS: Twelve patients with AS (mean (SD) age 44.9 (14.7) years) and 27 healthy controls (46.4 (12.8) years) were enrolled into the study. The expression of chemokine receptors (CCR-5, CXCR-3, CCR-4) and cytokines (interferon gamma (IFNgamma), interleukin (IL)2, IL4, IL10, tumour necrosis factor alpha (TNFalpha)) on CD28(+) and CD28(-) T cell subtypes was analysed by a three colour FACS technique of peripheral blood samples. Serum ELISAs were performed to detect the CCR-5 ligands CCL-5, CCL-3; the CXCR-3 ligands CXCL-10, CXCL-9; and the CCR-4 ligand, CCL-17 before and after administration of the TNFalpha blocking agent infliximab. RESULTS: CD4(+)CD28(-) T cells had higher ratios of CXCR-3 to CCR-4 than CD4(+)CD28(+) T cells. Both, CD4(+) and CD8(+)CD28(-) T cells of patients with AS produced more IFNgamma, TNFalpha, and IL10 than their CD28(+) counterparts (p<0.05), and lacked the production of IL2 and IL4. Serum levels of CXCL-9 were increased in patients with AS to 59.2 pg/ml (34.1-730.5) compared with 32.5 pg/ml (20.0-79.5) in healthy controls (p = 0.016). The levels of both type 1 (CCL-5, CXCL-9) and type 2 chemokines (CCL-17) decreased under blockade of TNFalpha (p<0.05). CONCLUSIONS: The profile of chemokine receptor expression and cytokine production by CD28(-) T cells suggests a type 1 immune reaction in AS, although IL10 is frequently produced by CD28(-) T cells. Treatment with TNFalpha blocking antibodies decreased both types of chemokines in patients' sera.

Vascular endothelial growth factor (VEGF) in ankylosing spondylitis--a pilot study.

INTRODUCTION: Angiogenesis is important for the pathogenesis of chronic inflammatory diseases in joints. Inflammation itself may upregulate the expression of VEGF in rheumatic diseases. Angiogenesis may become a new target for therapeutic intervention in inflammatory joint disease. AIM OF THE STUDY: To examine plasma levels of VEGF in AS patients and to test a possible correlation with serological and/or clinical parameters. PATIENTS AND METHODS: Sixteen consecutive patients with definite AS were recruited from the Gasteiner Heilstollen Hospital and compared to eight healthy probands as controls. VEGF was determined in EDTA plasma samples by using an ELISA kit. Data are given as mean values (+/- SEM). The Spearman two-sided test was used to test possible correlations. RESULTS: EDTA-plasma levels of VEGF were 75.3 +/- 19.0 pg/ml, compared to 13.8 +/- 4.7 pg/ml measured in the control group (P = 0.001). A significant correlation was found between plasma VEGF of AS patients and the BASMI score (r = 0.665, P = 0.013). Whereas VEGF was elevated in patients without treatment or NSAIDs (88.9 +/- 24.2 pg/ml), lower levels up to 43.8 pg/ml were found in patients treated with corticosteroids (34.7 +/- 4.0 pg/ml, P = 0.039). CONCLUSIONS: Disease status of AS appears to be associated with elevated VEGF plasma levels. Whether this reflects inflammation or a truly angiogenic pathomechanism requires further investigation.