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Defects in regulatory T (Treg) cells have been implicated in the pathogenesis of chronic inflammatory and autoimmune diseases, such as Wegener's granulomatosis (WG). This study aimed at evaluating numbers, phenotype and suppressive capacity of Treg cells in WG. Peripheral blood (PB) mononuclear cells from 22 WG-patients (17 active, 5 remission) and 22 sex- and age-matched healthy controls (HC) were examined for Treg cells by flow cytometry measuring CD4, CD25, transcription factor forkhead box P3 (FoxP3), chemokine receptor CCR4 and interferon receptor I (IFNRI). Suppressive function of CD4+CD25high Treg cells from 3 WG-patients and 3 HC was analysed using a carboxyfluoresceindiacetate-succinimidylester-based in vitro proliferation assay. Endonasal biopsies of 10 WG- and 5 sinusitis-patients were investigated for CD3+FoxP3+ cells, employing double immunohistochemistry. WG-patients displayed elevated numbers of CD4+CD25med T cells and of CD4+CD25high Treg cells. CD4+ T cells of WG-patients contained higher numbers of CCR4+ cells. However, CD4+CD25high Treg cells of WG-patients exhibited decreased numbers of cells co-expressing FoxP3 and CCR4. A low but significant increase of CD4+CD25highIFNRI+ Treg cells was detected in WG-patients. 9 days following stimulation with interferon (IFN)alpha + proteinase 3 (PR3), a reduced suppression of proliferation of responder T cells was observed for WG and proliferated CD4+CD25high Treg cells still showed downregulated co-expressions of FoxP3 and CCR4. Wegener's granuloma exhibited increased numbers of CD3+FoxP3+ cells. The results indicate upregulated numbers of Treg cells in PB and nasal mucosa as well as phenotypical and functional alterations of PB Treg cells in WG, some presumably mediated through PR3 and IFN-alpha.

NKG2D, involved in T-cell activation and viral defense, shows a single-nucleotide polymorphism (SNP) in the transmembrane region, characterized by a substitution of alanine with threonine. We examined the association of systemic lupus erythematosus (SLE) with one of the NKG2D gene variants. We also studied the functional impact of that allele in SLE. Restriction fragment length polymorphism/polymerase chain reaction specific for the SNP rs2255336 G--> A was performed with 247 German SLE patients and 447 controls and with 284 Spanish SLE patients and 180 controls. NKG2D expression on peripheral blood lymphocytes of SLE patients was analyzed via fluorescence activated cell sorter. In addition, proliferation assays were performed. We found that the NKG2D alanine/alanine (G/G) gene variant was significantly associated with SLE in the German cohort (70.4% vs 60.8% controls; p = 0.0027) and almost significantly in the Spanish cohort (66.2% vs 62.2% controls; p = 0.054). In a pooled analysis, the prevalence of G/G was 68.2% in SLE versus 61.2% in the controls (p = 0.0024). There were no significant differences in the expression levels of NKG2D on peripheral blood lymphocytes of the different genotypes. A comparison of the coreceptor activity of the genotypes in response to CD3 and NKG2D antibodies revealed a trend toward higher proliferation in the A/A genotype. In conclusion, based on our study results, SLE is associated with the SNP rs2255336 of NKG2D.

Objectives: While remission is achieved in the majority of Wegener's granulomatosis (WG)-patients with cyclophosphamide, maintenance of remission remains a challenge due to the high rate of relapses. The purpose of this study was to evaluate the safety and efficacy of the combination of methotrexate (MTX) plus leflunomide (LEF) for the treatment of minor relapsing WG not warranting cyclophosphamide., Methods: Retrospective chart analyses of 51 WG-patients with non-life-threatening relapses under MTX or LEF maintenance monotherapy. Relapsing patients were subsequently treated with a combination therapy of MTX+LEF., Results: Fifty-one WG patients with relapses under MTX (n=36) or LEF (n=15) maintenance monotherapy were identified. They were subsequently treated with MTX+LEF to reintroduce remission. Mean follow-up was 26.0 (3-93) months. MTX+LEF controlled relapsing WG in 43/51 (84%) patients: 28/51 achieved a Birmingham Vasculitis activity index (BVAS)=0 and 15/51 a response (BVAS reduction of > = or). 8/51 patients did not respond to MTX+LEF (<50% BVAS reduction) and were switched to cyclophosphamide and/or a biological for ongoing disease activity. Follow up showed a sustained remission (BVAS=0 >3 months) in 14/51 patients, a minor relapse in 27/51, and a major relapse in 2/51 (subsequently switched to cyclophosphamide). Fifty adverse effects were observed. MTX+LEF therapy was discontinued in 18/51 patients because of adverse effects (main causes: gastro-intestinal complaints, hypertension, infections)., Conclusions: Although side effects limited the overall performance of MTX+LEF, this combination, if tolerated well, remains an effective treatment in patients not warranting cyclophosphamide.

Objectives: The aim of this study was to analyse mPR3 expression on neutrophils in two Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV), namely WG (localised vs. generalised) and Churg-Strauss syndrome (CSS) and other inflammatory disorders, in order to evaluate (i) whether the pattern of mPR3 expression is specific for AAV and (ii) to assess whether the mPR3high status is associated with clinically distinct disease stages of WG (localised vs. generalised)., Methods: Localised WG (n=15), generalised WG (n=55), Churg-Strauss Syndrome (CSS) (n=20), systemic lupus erythematosus (SLE) (n=15), Rheumatoid Arthritis (RA) (n=22) and healthy controls (n=30) were analysed. mPR3 and CD63 expression on surface of neutrophils were assessed by flow cytometric analysis on isolated neutrophils and whole blood., Results: In patients with genWG and SLE, an increased percentage of mPR3+ neutrophils and an elevated level of mPR3 expression compared to healthy controls were found (percentage: p=0.001, p=0.000; MFI ratio: p=0.038, p=0.019, respectively). There was no increased frequency of mPR3+ neutrophils in CSS. Within the group of WG, an elevated level of mPR3 expression was significantly associated with disease stage (genWG and not locWG), and in genWG with disease activity and the presence of ANCA., Conclusions: The mPR3high status is associated with generalised WG and correlates with disease activity and ANCA status in generalised WG. An increased proportion of mPR3-positive neutrophils is not specific for AAV.

Objectives: The aim of the study was to assess PAR-2 expression on dendritic cell (DC) subsets and other immune cells of Wegener's granulomatosis (WG) patients and healthy controls (HC) and to investigate whether Proteinase 3 (PR3, a serine protease which can activate PAR2) induces maturation of human DC-like monocytes and murine Flt-3 ligand- and GM-CSF-generated DC., Methods: Human peripheral blood cells including DC subsets and Flt-3l- and GM-CSF-generated mouse DC were analysed for expression of PAR-2 and DC maturation markers by flow cytometry before and after stimulation with PR3, trypsin, PAR-2 agonist or LPS for 24 h., Results: There was no difference of PAR-2 expression on PMNs, monocytes, lymphocytes and DC between all WG samples and HC. However, in inactive WG, expression of PAR-2 was downregulated on the cell surface of PMNs, monocytes, lymphocytes, and CD11c+DC compared to active WG and HC. PR3 and PAR2-agonists did not induce upregulation of PAR-2 or maturation markers of human DC-like monocytes in WG and HC. Likewise, murine PR3 did not induce upregulation of PAR-2 or maturation markers in murine DC., Conclusions: PAR-2 expression is downregulated on human peripheral blood cells including CD11c+ DC in inactive WG compared to active WG and HC, possibly reflecting a non-activated status of these cells in inactive disease. PR3 and PAR-2- agonists did not induce maturation of human ex vivo DC-like monocytes in WG and HC and of murine DC, suggesting this pathway is not singularly involved in the maturation of these cell subsets.

Objectives: Nasal colonisation with Staphylococcus aureus (S. aureus) has been implicated in Wegener's granulomatosis (WG) disease activity. In this study, the frequency of nasal colonisation with S. aureus in WG was compared to healthy and disease control groups for the first time. Moreover, endonasal activity was correlated to colonisation., Patients and Methods: Nasal carriage of S. aureus of a well-defined group of 89 patients with WG was compared to 40 patients with chronic rhinosinusitis with nasal polyps (CRS), 35 patients with rheumatoid arthritis (RA), 50 hospital staff members and 25 subjects without regular hospital contact and correlation analysis of nasal carriage and endonasal activity of WG was performed., Results: WG patients showed significantly higher rates (72%) of nasal colonisation with S. aureus compared to CRS patients (28%) and healthy subjects without regular hospital contact (25%, 95%-CI), but not to RA patients (46%) and hospital staff members (58%). WG patients with nasal carriage of S. aureus had significantly higher endoscopically proven endonasal activity (p=0.01), significantly more often first manifestation of WG in the upper respiratory tract (p=0.02) and higher relapse-rates (p=0.052) than WG patients without such carriage., Conclusions: Endonasal activity in WG is associated with higher nasal S. aureus colonisation rates and subsequent higher relapse rates. The higher frequency of S. aureus colonisation could be a consequence of a recently shown mucosal barrier defect in WG and facilitate chronic inflammation and granuloma formation in the upper respiratory tract.

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) comprise the most common group of primary systemic vasculitides and include Wegener;s granulomatosis (WG), microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS), and renal-limited vasculitis (RLV). AAV share the feature of necrotizing predominantly small vessel vasculitis, but are otherwise distinct diseases with differences in the genetic background, epidemiological and exogenous factors, immune and pathologic features, preferences of organ involvement, and frequencies of ANCA-association. MPA and RLV display solely vasculitic features, whereas WG and CSS are characterized by both granulomatous disease and a systemic vasculitis. Chronic inflammation and neoformation of tertiary lymphoid tissue appear to initiate and maintain the break of tolerance and induction of ANCA in AAV. A number of mechanisms are implied in this process, e.g., nasal S. aureus carriage suggestive of a potential link to infection in WG, danger-signals, neutrophil extracellular traps (NETs), the protease-activated receptor (PAR)-2, cytokines (Th1/Th2-type, IL-15, IL-17), and NK-like T-cells. The outcome of AAV has greatly improved since the introduction of immunosuppressive therapy. Still, the prognosis is impaired by high relapse rates and side effects of immunosuppressive therapy. Biologicals emerged as a new class of drugs that may help to improve outcome and reduce side effects of conventional treatments. So far, anti-CD20 therapy (rituximab) and TNF-alpha-antagonists represent strategies for refractory disease, but evidence from controlled trials is still lacking. Controlled trials for "routine" remission induction with these biological are also pending. New therapy principles hold further promise for the future.

This article focuses on the clinical application and technical aspects of imaging methods which are used alternatively or additionally to angiography or magnetic resonance imaging in patients with Takayasu's arteritis or giant cell arteritis. Providing a high spatial resolution, duplex ultrasound is particularly suitable for the evaluation of peripheral arteries. With the exception of cranial arteries, positron emission tomography as a whole body examination is the best imaging modality for the assessment of inflammatory activity. Computed tomography is used for angiographic examinations and enables evaluation of wall thickening in large arteries. It is the method of choice in the case of emergencies due to aortic aneurysm or dissection. In addition to angiographic and ultrasound techniques, ophthalmological methods comprise biomicroscopy, including funduscopy and optical coherence tomography.

Churg-Strauss syndrome is a rare small-vessel vasculitis that is associated with asthma, granulomatous inflammation, peripheral/tissue eosinophilia and a positive antineutrophil cytoplasmic antibody status (in approximately 40% of patients). The disease can be organ- and life-threatening, either due to tissue eosinophil infiltration such as myocarditis or due to vasculitis manifestations, for example glomerulonephritis. Furthermore, life-threatening disease can also occur due to the side effects of immunosuppression, for example, infection. A thorough diagnostic work-up should be performed in order to identify all organs involved and to rule out other disorders with similar features, such as hypereosinophilic syndrome. Therapeutic management is conducted according to disease stage and activity. Glucocorticoids remain the mainstay of therapy; however, further immunosuppressants (e.g., cyclophosphamide for life-threatening disease) are usually required. Future promising therapy options target cytokines involved in the disease process, such as IL-5.

Giant cell arteritis and Takayasu's arteritis are classified as primary large-vessel vasculitides. Inflammatory cell infiltrates and cytokines induce destruction and hyperplasia of the vessel wall, leading to stenoses or aneurysms. When extracranial large arteries are involved, there is often a similar clinical and radiologic disease pattern of an inflammatory aortic arch syndrome. Rare causes of large-vessel vasculitis include Behçet's disease, association with other autoimmune diseases, and infection. Depending on the localization, imaging is usually performed by means of duplex ultrasound, magnetic resonance imaging, computed tomography, or positron emission tomography. These imaging modalities are used not only to establish the diagnosis but also to determine the disease extent and activity and to perform follow-up in the course of medical therapy. Angiography offers the option to perform interventional therapy for vascular stenoses and occlusions.

We reported earlier that two mitochondrial gene polymorphisms, UCP2 -866 G/A (rs659366) and mtDNA nt13708 G/A (rs28359178), are associated with multiple sclerosis (MS). Here we aim to investigate whether these functional polymorphisms contribute to other eight chronic inflammatory diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Wegener' granulomatosis (WG), Churg-Strauss syndrome (CSS), Crohn's disease (CD), ulcerative colitis (UC), primary sclerosing cholangitis (PSC) and psoriasis. Compared with individual control panels, the UCP2 -866 G/A polymorphism was associated with RA and SLE, and the mtDNA nt13708 G/A polymorphism with RA. Compared with combined controls, the UCP2 -866 G/A polymorphism was associated with SLE, WG, CD and UC. When all eight disease panels and the original MS panel were combined in a meta-analysis, the UCP2 was associated with chronic inflammatory diseases in terms of either alleles (odds ratio (OR)=0.91, 95% confidence interval (95% CI): 0.86-0.96), P=0.0003) or genotypes (OR=0.88, (95% CI: 0.82-0.95), P=0.0008), with the -866A allele associated with a decreased risk to diseases. As the -866A allele increases gene expression, our findings suggest a protective role of the UCP2 protein in chronic inflammatory diseases.

Recently, there has been increasing evidence that a non-synonymous exchange (Gly307Ser) in the gene for CD226 is linked to several autoimmune diseases including type 1 diabetes, multiple sclerosis (MS), rheumatoid arthritis and Grave's disease. Here we present evidence that this polymorphism also predisposes to Wegener's granulomatosis (WG), an autoimmune condition belonging to the group of ANCA (antineutrophil cytoplasmic autoantibody)-associated vasculitides. We found a significant association of the 307Ser allele in separate panels of 520 Northern German (P=0.016, odds ratio (OR)=1.20) and 122 Southern German (P=0.020, OR=1.37) WG cases compared with 1226 healthy controls. The importance of this single-nucleotide polymorphism in the etiopathology of ANCA-associated vasculitides is supported by similar effect sizes that we found in British WG cases (n=105) and German patients with Churg-Strauss syndrome (n=119), which, however, miss significance level because of the relatively small cohorts available for these rare disorders. Finally, we confirm the association with MS in a cohort of 422 German patients (P=0.011, OR=1.23).

Imaging methods have become indispensable for the diagnosis and follow-up of giant cell arteritis and Takayasu's arterititis, in addition to physical examination and laboratory parameters. The choice of method is predominantly determined by clinical presentation and localization of the vascular territory to be examined. Furthermore, aspects of radiation protection, contrast media intolerance and other contraindications, as well as the varying costs of the different procedures need to be considered. This article reviews the clinical and morphological features of primary large vessel vasculitides which are fundamental to the identification of the disease and the assessment of inflammatory activity using imaging modalities. Angiography is the gold standard for the evaluation of stenotic lesions and can be combined with interventional treatment. Vessel wall thickening as a defining diagnostic criterion is outlined only by cross-sectional imaging. In addition to MR angiography, MRI techniques in particular enable vizualization of inflammatory processes in central as well as in peripheral arteries.

In its strict sense, the term "autoinflammatory syndromes" comprises the hereditary periodic fever syndromes (HPF), which are caused by mutations of pattern-recognition receptors (PRR) and perturbations of the cytokine balance. These include the crypyrinopathies, familial Mediterranean fever, TNF-receptor associated periodic fever syndrome (TRAPS), hyper-IgD and periodic syndrome (HIDS), pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, NALP12-HPF, and the Blau syndrome. The diseases are characterized by spontaneous activation of cells of the innate immunity in the absence of ligands. Autoantibodies are usually not found. HPF clinically present with recurrent fever episodes and inflammation, especially of serosal and synovial interfaces and the skin. Intriguingly, PRR-mediated autoinflammtory mechanisms also play a role in a number of chronic inflammatory and autoimmune diseases.

Objective: The pathogenesis of granulomatous inflammation in the respiratory tract and autoimmunity in Wegener granulomatosis (WG) are poorly understood. Since mucociliar clearance represents the first major line of defence in the respiratory tract and its breakdown facilitates chronic inflammation, we investigated ciliary beat frequency (CBF) in WG., Methods: Nasal epithelial cells were obtained from 30 patients with WG with involvement of the upper respiratory tract, 12 patients with other inflammatory rheumatic disease and 10 healthy controls. CBF was measured at 5 and 24 h after collection., Results: were correlated with clinical data. Results: CBF was significantly reduced in WG compared to disease and healthy controls after 5 and 24 h. In WG, CBF almost stagnated after 24 h. Reduction of CBF correlated with the cumulative number of immunosuppressive agents in WG, but not in disease controls. No correlation was found between CBF impairment and cyclophosphamide levels, disease extent, disease activity, disease duration, serological and microbiological findings, or inflammation markers., Conclusion: CBF is severely impaired in WG, potentially influenced by immunosuppressive treatment. To what extent CBF impairment and subsequent barrier dysfunction are caused by other factors still has to be elucidated. Supportive measures to improve mucociliary clearance should be discussed in patients with WG.

Small-vessel vasculitis (SVV) is a chronic autoinflammatory condition linked to antineutrophil cytoplasm autoantibodies (ANCAs). Here we show that chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulated neutrophils and contain the targeted autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO). Deposition of NETs in inflamed kidneys and circulating MPO-DNA complexes suggest that NET formation triggers vasculitis and promotes the autoimmune response against neutrophil components in individuals with SVV.

A lot of progress has been made regarding the therapy of ANCA-associated vasculitides in the past decades. Cyclophosphamide still is standard therapy for remission induction in generalized disease, however, duration and cumulative dose of cyclophosphamide have been curtailed successfully to reduce toxicity. MTX is a safe alternative for remission induction in early systemic disease and medications available for remission maintenance have been extended. Rituximab and TNFalpha-antagonists represent promising options for refractory disease. The current evidence of therapy of ANCA-associated vasculitides is summarized in this review.

Whether we like it or not, medicine is big business. The argument is sometimes made that standard management strategies from the business world do not apply to medicine because the economics and practice of medicine are unique--driven by science and rapid rates of change. But an exploding knowledge base, light-speed technological development, and ever-changing reimbursement schemes are not exclusive to medicine and health care. Some fundamental principles of finance, business management, and strategic development have evolved to deal with problems of rapid change. These principles do apply to modern medicine. The business side of anesthesia practice is off-putting to many clinicians. However, knowledge of the market forces at play can help enhance patient care, improve service, expand opportunities, and extend the perimeter of the discipline. The mission and current market position of anesthesiology practice are considered here.

Recently, the European League Against Rheumatism (EULAR) published recommendations on the management of patients with primary systemic vasculitides. The use of the given definitions for different activities and stages of the diseases is encouraged not only in clinical trails but also for the purpose of harmonisation in daily routine. Concerning the diagnostic work-up an interdisciplinary approach in co-operation with expert-centre is recommended. Therapy consists of remission induction and maintenance. For induction therapy in small vessel vasculitis cyclophosphamide or medium potent immunosuppressants such as methotrexate plus glucocorticoids should be used according to disease stage and activity. Glucocorticoids also represent the mainstay of remission induction in large vessel vasculitis. Additional immunosuppressants should be considered, if the disease can not be controlled by glucocorticoids or for the purpose of sparing glucocorticoids. Refractory disease should be treated within clinical trails. Further recommendations deal with monitoring of diseases activity and therapy as well as with measures to avoid complications and late sequelae.

A major genomic region involved in Wegener's granulomatosis includes the gene for retinoid receptor beta (RXRB) which forms heterodimers with peroxisome proliferator-activated receptors (PPARs). It is unclear whether this association directly arises from the RXRB allele(s) or via a linked variation. In order to reveal any hitherto unknown and potentially disease-relevant variation of the RXRB gene, we have genotyped four tagging SNPs of this genomic region and have directly sequenced selected WG patients and controls representing disease-associated haplotypes. Additionally, we have genotyped 2 SNPs each in the genes for PPARα and PPARγ (PPARA and PPARG). Hence, we confirmed the strong association of the RXRB locus with WG but could not reveal any novel variation in RXRB. None of the PPARA and PPARG SNPs showed association with WG. Moreover, no epistatic effect was seen between RXRB and PPARA/PPARG alleles. These results do not support an etiopathological role of PPAR in WG. Analyses of further genes functionally linked to RXRB may provide additional data useful to evaluate the RXRB association found in WG.

Although infections are a major concern in patients with primary systemic vasculitis, actual knowledge about risk factors and evidence concerning the use of anti-infective prophylaxis from clinical trials are scarce. The use of high dose glucocorticoids and cyclophosphamide pose a definite risk for infections. Bacterial infections are among the most frequent causes of death, with Staphylococcus aureus being the most common isolate. Concerning viral infections, cytomegalovirus and varicella-zoster virus reactivation represent the most frequent complications. The only prophylactic measure that is widely accepted is trimethoprim/sulfamethoxazole to avoid Pneumocystis jiroveci pneumonia in small vessel vasculitis patients with generalised disease receiving therapy for induction of remission.

Increased amounts of anti-neutrophil cytoplasm antibody (ANCA) directed against proteinase 3 (PR3) are a diagnostic and pathogenic hallmark of full-blown Wegener's granulomatosis (WG). Aggregates of B lymphocytes proximal to PR3+ cells as well as plasma cells have been described as substantial components of Wegener's granuloma and could participate in forming tertiary lymphoid structures, which might promote autoantibody formation. Our aim was a molecular analysis of single B cells in order to develop a methodological approach that allows examination of potential ANCA formation in the tissue. Single B cells from cryo-conserved endonasal biopsies of three WG patients were isolated, using laser-assisted microdissection. Subsequently, their immunoglobulin variable heavy (VH) and light (Vkappa, Vlambda) chain genes were analysed by single cell polymerase chain reaction and direct sequencing. Sixteen immunoglobulin VH-Vkappa or VH-Vlambda chain gene couples were characterized. Twelve of these immunoglobulin gene couples resembled memory B cells. Two offsprings of one B cell were detected, indicating clonal expansion. VH genes representing 39 single B cells of WG tissues displayed significantly more mutations when compared with VH genes from peripheral blood of a healthy donor. The findings confirm and extend our previous results, arguing for an initial selection and affinity maturation of B cells within Wegener's granuloma. Further, the methodology provides the initial basis for the recombinant generation of antibodies derived from tissue cells.

In the last few years, substantial progress has been achieved in elucidating the pathogenesis of Wegener's granulomatosis. Several genetic risk factors have been described. The structure of the granuloma and its possible function as ectopic lymphoid tissue have been defined. Furthermore, the consecutive immunopathological reactions leading to induction of PR3-antineutrophil cytoplasmic antibodies (ANCA) and the role of ANCA itself is getting clearer. However, the initial events leading to granuloma formation are still widely unknown. Concerning therapy, the significance of the so-called biological agents (TNF-alpha-blockers, Rituximab) still has to be defined.

Schnitzler syndrome describes the simultaneous occurrence of monoclonal gammopathy and chronic urticaria with at least two additional minor symptoms (arthralgia, bone pain, fever of uncertain origin, hepato- or splenomegaly, lymphadenopathy, increased erythrocyte sedimentation rate, leukocytosis/thrombocytosis or increased bone density). Schnitzler syndrome is not wellknown and very likely under-recognized. Comprehensive diagnostic examinations are necessary to rule out other diseases, especially those of hematologic origin. Close interdisciplinary collaboration is mandatory. The etiology of Schnitzler syndrome is unclear, but the rapid response to the interleukin-1 receptor inhibitor anakinra underlines the pivotal role which the proinflammatory cytokine interleukin-1 may play in the pathophysiology of this potentially autoinflammatory disorder.

Background: There has been some concern that leucotriene receptor antagonists might precipitate the onset of Churg-Strauss syndrome (CSS). A study was undertaken to investigate the relationship between the leucotriene receptor antagonist montelukast and the onset of CSS., Methods: Medication histories of 78 patients with CSS from France and Germany were retraced by questioning the patients, treating physicians and dispensing pharmacists, and from medical records. Using a case-crossover research design, exposures to montelukast and other asthma medications during the 3-month "index" period immediately preceding the onset of CSS were compared with those of four previous 3-month "control" periods. Odds ratios (ORs) were computed by conditional logistic regression., Results: The ORs for CSS onset were 4.5 (95% CI 1.5 to 13.9) for montelukast, 3.0 (95% CI 0.8 to 10.5) for inhaled long-acting beta(2) agonists, 1.7 (95% CI 0.5 to 5.4) for inhaled corticosteroids and 4.0 (95% CI 1.3 to 12.5) for oral corticosteroids. Montelukast exposure during control periods increased temporally over three consecutive calendar periods of CSS onset from 1999 to 2003 (p(trend) <0.0001)., Conclusion: Montelukast use was associated with a 4.5-fold higher risk of CSS onset within 3 months. However, the positive estimates obtained for other long-term asthma control medications suggest that this link might be confounded by a general escalation of asthma therapy before CSS onset. The association between montelukast and CSS observed in this study is probably also explained by the increasing use of this medication over time.

Objective: Systemic sclerosis (SSc) is a rare, heterogeneous disease, which affects different organs and therefore requires interdisciplinary diagnostic and therapeutic management. To improve the detection and follow-up of patients presenting with different disease manifestations, an interdisciplinary registry was founded with contributions from different subspecialties involved in the care of patients with SSc., Methods: A questionnaire was developed to collect a core set of clinical data to determine the current disease status. Patients were grouped into five descriptive disease subsets, i.e. lcSSc, dcSSc, SSc sine scleroderma, overlap-syndrome and UCTD with scleroderma features., Results: Of the 1483 patients, 45.5% of patients had lcSSc and 32.7% dcSSc. Overlap syndrome was diagnosed in 10.9% of patients, while 8.8% had an undifferentiated form. SSc sine scleroderma was present in 1.5% of patients. Organ involvement was markedly different between subsets; pulmonary fibrosis for instance was significantly more frequent in dcSSc (56.1%) than in overlap syndrome (30.6%) or lcSSc (20.8%). Pulmonary hypertension was more common in dcSSc (18.5%) compared with lcSSc (14.9%), overlap syndrome (8.2%) and undifferentiated disease (4.1%). Musculoskeletal involvement was typical for overlap syndromes (67.6%). A family history of rheumatic disease was reported in 17.2% of patients and was associated with early disease onset (P < 0.005)., Conclusion: In this nationwide register, a descriptive classification of patients with disease manifestations characteristic of SSc in five groups allows to include a broader spectrum of patients with features of SSc.

Objectives: We undertook a systematic literature review as a background to the European League Against Rheumatism (EULAR) recommendations for conducting clinical trials in anti-neutrophil cytoplasm antibody associated vasculitis (AAV), and to assess the quality of evidence for outcome measures in AAV., Methods: Using a systematic Medline search, we categorised the identified studies according to diagnoses. Factors affecting remission, relapse, renal function and overall survival were identified., Results: A total of 44 papers were reviewed from 502 identified by our search criteria. There was considerable inconsistency in definitions of end points. Remission rates varied from 30% to 93% in Wegener granulomatosis (WG), 75% to 89% in microscopic polyangiitis (MPA) and 81% to 91% in Churg-Strauss syndrome (CSS). The 5-year survival for WG, MPA and CSS was 74-91%, 45-76% and 60-97%. Relapse (variably defined) was common in the first 2 years but the frequency varied: 18% to 60% in WG, 8% in MPA, and 35% in CSS. The rate of renal survival in WG varied from 23% at 15 months to 23% at 120 months., Method: used to assess morbidity varied between studies. Ignoring the variations in definitions of the stage of disease, factors influencing remission, relapse, renal and overall survival included immunosuppressive therapy used, type of organ involvement, presence of ANCA, older age and male gender., Conclusions: Factors influencing remission, relapse, renal and overall survival include the type of immunosuppressive therapy used, pattern of organ involvement, presence of ANCA, older age and male gender. Methodological variations between studies highlight the need for a consensus on terminology and definitions for future conduct of clinical studies in AAV.

Tumor necrosis factor (TNF-alpha) plays an essential role in the orchestration of inflammatory processes including autoimmune disorders, host defence and granuloma formation. TNF antagonists are highly effective in the therapy of rheumatoid arthritis, but they compromise host defence mechanisms, especially concerning bacterial infections inducing granuloma formation, such as tuberculosis. Other biologics have been developed and approved for the therapy of rheumatoid arthritis, e.g. an interleukin (IL-1) blocking agent (anakinra), an antibody that depletes CD20 positive B-cells (rituximab) and an inhibitor of T-cell co-stimulation (abatacept). In spite of initial skepticism regarding side effects, such as an increased risk of infections, biologics now play an essential role in the therapy of autoimmune diseases due to the implementation of efficient screening measures concerning side effects (such as reactivation of tuberculosis). This review summarizes the current available data regarding risk of infection and gives and overview on recommended screening, contraindications and events that require withdrawal of therapy.

Objectives: To evaluate the use of MRI and FDG-PET for the diagnosis and measurement of disease activity of inflammatory aortic arch syndrome in patients with complicated giant cell arteritis., Methods: MRI and FDG-PET were performed for 25 patients with giant cell arteritis who presented with a complicated disease course despite immunosuppressive therapy. Disease activity of the thoracic aorta and the supra-aortic arteries as assessed by both modalities was compared with serological (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)) and clinical findings (Birmingham vasculitis activity score (BVAS.2)). Additionally, the usefulness of MRI for assessment of vessel wall thickening, aneurysms and stenoses was evaluated., Results: In 17/25 patients, MRI disclosed structural vessel lesions suspicious for vasculitis. Active disease was detected by MRI, thoracic PET, and whole body PET in 22, 14 and 20 patients, respectively. While serological and clinical findings correlated significantly with each other, there was no concordance with MRI and only low, non-significant correlation of PET with CRP (r(s) = -0.158, 0.136), ESR (r(s) = -0.232, 0.320) and BVAS.2 (r(s) = -0.064, 0.221) for disease activity., Conclusions: MRI and PET are unreliable for assessing large-vessel inflammation in patients with giant cell arteritis and pre-existing immunosuppressive therapy. MRI is valuable for its ability to detect morphological vessel lesions, such as aneurysms and stenoses.

Background: A genomic region on chromosome 6p21.3, including HLA-DPB1, has been linked to Wegener's granulomatosis (WG). The basis of this association is difficult to evaluate because of the complex haplotype block architecture of this region., Objective: To identify the causative molecular genetic variation(s) using a detailed HapMap based fine-mapping approach., Methods: 282 patients with WG and 380 healthy controls were genotyped for HLA-DPB1 as well as for 35 informative single nucleotide polymorphisms (SNPs) within the respective region. 25 of these SNPs have been selected as tagging SNPs for another 219 associated SNPs. Allele and genotype frequencies were analysed separately by contingency tables and logistic regression. Finally, the coding region of RING1 was directly sequenced in subjects who carried haplotypes that were correlated with contrasting WG risks., Results: The previously reported strong association of WG with the HLA-DPB1*0401 allele was confirmed in an independent WG sample (n = 108, p(c) = 6.4 x 10(-8)). When the complete cohort (n = 282) was considered, the association remained highly significant in ANCA-positive (p(c) = 1.26 x 10(-22)), but not in ANCA-negative patients. An SNP 3' of HLA-DPB1 yielded the smallest p value and was associated with WG partly independently from the HLA-DPB1 alleles. Another informative SNP in the vicinity of RING1 showed significant WG association that was also partly independent of HLA-DPB1. RING1 sequencing, however, did not show any variation potentially predisposing to WG., Conclusions: The HLA-DPB1/RING1 region is strongly associated with WG in ANCA-positive subjects. Further analyses of potential cis regulatory sequences of candidate genes HLA-DPB1, RING1 and RXRB appear warranted.

Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome are idiopathic systemic vasculitides in which circulating anti-neutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) or myeloperoxidase (MPO) are commonly found. Within the last 25 years, these antibodies were subject of intensive studies, and a growing body of evidence arose for a distinct role of ANCA in the pathogenesis of the ANCA-associated vasculitides (AAV). Yet, the evidence derived from clinical observations and in vitro studies remains circumstantial. The various animal models have provided substantial support for a pathogenic role of MPO-ANCA in vivo, but the debate if ANCA play a primary role in the pathogenesis of these diseases is still open. The aim of this review was to update current basic and clinical research on ANCA in the pathophysiology of AAV and to point out and discuss limitations and inconsistencies of the clinical and experimental evidence.

Objective: Wegener's granulomatosis (WG) and Churg-Strauss syndrome (CSS) belong to the heterogeneous group of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Current understanding of their pathogenesis and genetic background is limited. Expression levels of interleukin-10 (IL-10), a potent and pleiotropic cytokine, are largely determined by variations in the gene encoding the IL-10 precursor. This study was undertaken to determine the impact of IL10 polymorphisms on the pathogenesis of both WG and CSS in large cohorts., Methods: Three single-nucleotide polymorphisms (SNPs) tagging the promoter haplotypes of the IL10 gene (IL10 -3575, IL10 -1082, and IL10 -592) were analyzed in 403 patients with WG and 103 patients with CSS as well as 507 matched control subjects from Germany. In addition, 3 informative SNPs in other parts of IL10 were genotyped., Results: None of the markers or their haplotypes was associated with WG or any of its subgroups classified according to ANCA status, sex, or presence of further WG genetic risk factors. In contrast, the IL10 -3575/-1082/-592 TAC haplotype, part of the extended ancient haplotype IL10.2, was highly significantly associated with ANCA-negative CSS (chi2 = 19.14, P = 0.000012, corrected P = 0.0003, odds ratio 2.16, 95% confidence interval 1.52-3.06)., Conclusion: These findings challenge those from previous studies of IL10 in WG and provide further evidence that CSS and WG have distinct genetic backgrounds. Because the IL10.2 haplotype has been correlated reproducibly with increased IL10 expression, the possible role of IL-10 in the pathogenesis of ANCA-negative CSS needs to be further elucidated.

Objective: Uncontrolled vasculitis is the major cause of early death in Churg-Strauss syndrome and standard therapy is not always effective. This study was carried out to examine the safety and efficacy of interferon-alpha for induction of remission in patients with refractory Churg-Strauss syndrome., Methods: In a prospective open-label trial, seven patients with Churg-Strauss syndrome refractory to cyclophosphamide or methotrexate received interferon-alpha (3 million. I.U. 3 times weekly s.c.) for induction of remission. Primary end point was the successful induction of remission. Prednisolone was tapered according to the study protocol., Results: All seven patients entered remission after 3 months of treatment. Five patients reached complete remission while in two patients, residual asthmatic complaints persisted. The mean Birmingham Vasculitis Activity Score (BVAS) decreased from 6.4 (+/-2.8) to 0 (+/-0) (p=0.017). Clinical improvement in response to interferon-alpha allowed to taper concomitant prednisolone according to the protocol from a mean dose of 20.4 mg/d (+/-13.3) to 6.9 mg/d (+/-1.9) (p=0.068). During a follow up of 6 months all patients remained in remission. In one patient, leukencephalopathy without clinical symptoms was seen on MRI after 61 months of treatment, as previously reported. In this cohort, no other cases of leukencephalopathy were observed during long-term follow-up. Constitutional symptoms related to the injection of interferon-alpha responded well to paracetamol. A transient leukopenia was found in two patients., Conclusion: Interferon-alpha appears to be an effective and well-tolerated treatment for induction of remission in patients with refractory Churg-Strauss syndrome.

According to the literature it is known that structured standardized patient education represents an effective additional treatment in patients with chronic diseases. Positive effects in the reduction of disease activity and depression have been shown for rheumatoid arthritis, systemic lupus erythematodes, and diabetes mellitus. An interdisciplinary approach for providing information was developed for patients with primary systemic vasculitides (PSV) in the vasculitis center in Bad Bramstedt. The contents of the seminars were revised and condensed into five modules. To evaluate the new form of the program a documentation system was designed. Patients were trained in closed groups (n=10-15) and completed the questionnaires at baseline, 4 weeks, 6 and 12 months following participation. A total of 102 patients in 10 closed groups showed a statistically significant increase in their knowledge in the three aspects of medicine, therapy and side effects, nutrition and physiotherapy. Health-related quality of life in all dimensions increased considerably. Both self-efficacy and the patient-assessed health status improved. The standardized structured education program for vasculitis patients provides an additional treatment in the interdisciplinary care of vasculitis.

Expansion of circulating CD28- T-cells reminiscent of effector memory T-cells (T(EM)) has been reported in Wegener's granulomatosis (WG) recently. To investigate the role of T(EM) in WG, we analyzed the expression of the activating NK-receptor NKG2D and its ligand MIC on circulating T(EM) and in granulomatous lesions, respectively. NKG2D was anomalously expressed and preferentially detected on circulating CD4+CD28- T(EM) in WG. Compared to healthy controls, T(EM) display a more activated phenotype potentially favoring unbalanced proinflammatory responses in WG. Cluster-like formations of "Wegener's autoantigen" PR3 were surrounded by NKG2D+ and NKG2D-ligand MIC+ cells in WG-granulomata, but not in disease controls. Further, IL-15 - known to drive T(EM) differentiation and proliferation--was also expressed in WG-granulomata. Thus, through acquisition of NK-like "innate" properties, IL-15 stimulated NKG2D+ T(EM) could interact with MIC+ cells within WG-granulomata, thereby sustaining inflammation and autoimmunity and promoting self-perpetuating pathology in WG.

Proteinase 3 (PR3) is a multifunctional neutrophil-derived serine protease influencing cell cycle, differentiation, and cell death. This molecule is the main target antigen of autoantibodies in Wegener's granulomatosis (WG) known as antineutrophil cytoplasmic antibodies (PR3-ANCA). WG usually starts as granulomatous inflammation of the upper respiratory tract (localized phase) and progress to systemic disease with PR3-ANCA-associated vasculitis (generalized phase). PR3-ANCA is thought to play a critical role in the pathogenesis of vascular damage in WG. In contrast, it is not clear how the granulomatous inflammation, the hallmark of WG, is driven, and what is the relationship between granuloma and autoimmunity. Recent findings provide evidence that PR3 might function as endogenous "danger/alarm" signal that communicates the presence of tissue injury to dendritic cells (DC) via protease-activated receptor-2 (PAR-2), triggers their maturation and instructs DC to induce Th1-type cell responses in WG. Furthermore, PR3 has the capacity to bind and activate IL-32, a recently discovered proinflammatory cytokine that has emerged as an important player in innate and adaptive immune response.Collectively, these results delineate new pathogenic pathways at the molecular level and provide insights into the mechanisms by which PR3 may contribute to the early pathogenesis of WG supporting the pivotal role of the interaction of Wegener's autoantigen with the "gateway" receptor PAR-2 in mediating both innate and adaptive immune response in WG.

Introduction: The authors present data on the incidence of primary systemic vasculitides (PSV) in the northern German state of Schleswig-Holstein from 1998 to 2005., Methods: Population-based study of all new cases of PSV from 1 January 1998 onward in a region with a population of 2.83 million. The sources of patient data were all hospital departments in the catchment area, including outpatient clinics; all departments of pathology; and the reference immunological laboratories serving the catchment area., Results: Over this eight-year period, 982 patients with newly diagnosed PSV were identified in Schleswig-Holstein, of whom 273 were diagnosed with ANCA (i.e., anti-neutrophil cytoplasmic antibody)-associated vasculitis (AAV). The incidence of all types of PSV combined was between 38 and 54 cases per million population per year. The incidence of AAV (which includes Wegener's granulomatosis [WG], microscopic polyangiitis [MPA], and Churg-Strauss syndrome [CSS]) was between 9.5 and 16 cases per million per year. WG consistently accounted for two-thirds to three-quarters of all new cases of AAV diagnosed each year., Discussion: This population-based vasculitis registry designed to capture all new cases of PSV in an eight-year period in a northern German region with 2.83 million inhabitants revealed stable incidence figures for all types of PSV and for AAV. Compared to figures obtained in other studies from small regions or referral centers, the incidence rate of WG (as an illustrative type of AAV) in this study was the same as those in Norway and Sweden, lower than that in the United Kingdom, but higher than those in Spain and in Vilnius (Lithuania). It is unclear whether these differences truly reflect a north-south gradient within Europe or are merely due to methodological differences.

Background and Objectives: While acral ischemia and necrosis represent a common problem in connective tissue diseases and other disorders, acral ischemic lesions are also occasionally encountered in primary and secondary systemic vasculitides. Here we report on the course of 4 patients with acral ischemic lesions as a hallmark of unclassified vasculitis. We compare these cases with 4 additional cases of acral ischemia complicating classified vasculitis., Objectives: To report on our experience with cases of unclassified vasculitis and acral ischemic lesions during the past 5 years and review the literature on vasculitis and acral ischemic lesions., Methods: The case history of one of the patients with unclassified vasculitis and acral ischemic lesions is reported in detail. The Medical history of another 3 patients presenting with vasculitic acral ischemic lesions and unclassified vasculitis during the past 5 years in our department (Lübeck/Bad Bramstedt) is summarized and compared to the course of patients with acral ischemic lesions complicating classified vasculitides. A PubMed database review of reports on acral ischemic lesions and vasculitis from 1985 to August 2006 was performed using the following combination of keywords: "Vasculitis" [MeSH] AND ("Necrosis" [MeSH] OR "Ischemia" [MeSH] OR "Infarction" [MeSH]) AND ("Extremities" [MeSH] OR "Fingers [MeSH] OR "Toes" [MeSH] OR "limb"), yielding 1328 entries. This search was subsequently limited to "Humans, All Adult (19+ years)", yielding 904 entries. Only three (0.7%) of these entries described one (one paper) or more (n=28) patients (two papers) with idiopathic vasculitis characterized by digit necrosis in the absence of systemic manifestations (except in some cases for arthralgia) or laboratory parameters pointing to a diagnosis of an established type of vasculitis., Results: A 37-year-old female presented with acral ischemic lesions of the left forefoot, fingers and toes, and Raynaud's phenomenon. Angiography showed multiple stenoses of ulnar and digital arteries, anterior and posterior tibialis arteries, and occlusions of radial artery and occlusion of the plantar artery in the absence of large vessel abnormalities. Histological analysis of an amputation disclosed giant cell arteritis of small vessels. The patient achieved remission with immunosuppressive treatment (cyclophosphamide and prednisolone). Three other patients with acral ischemic lesions and unclassified vasculitis also lacking other manifestations and defining laboratory and technical features during initial presentation and follow-up of 4 month to 5 years are presented. Necrotizing and leukocytoclastic vasculitis were present in two other patients, respectively. In contrast, acral ischemic lesions could be attributed to rheumatoid vasculitis and essential cryoglobulinemic vasculitis in two other cases each based on the patient's history and laboratory findings at the time of presentation of acral ischemic lesions., Conclusions: While acral ischemic lesions could represent initial or isolated (forme fruste) manifestations of a defined vasculitis, acral ischemic lesions may rarely be encountered as the predominant manifestation of an as yet unclassified vasculitis. the histological findings seem to differ. Our report includes a peculiar case of giant cell arteritis of small arteries not classifiable as giant cell arteritis of large arteries or Takayasu disease.

Churg-Strauss syndrome and the hypereosinophilic syndrome share many clinical features, particularly in the early disease stages. Beside blood and tissue eosinophilia, peripheral neuropathies, cutaneous manifestations, eosinophilic alveolitis and gastroenteritis are frequently found. In contrast to the hypereosinophilic syndrome, Churg-Strauss syndrome is defined by the presence of systemic vasculitis. However, frequently symptoms related to eosinophilia are (mis)interpreted as indirect signs of vasculitis. New treatment modalities and diagnostic methods render the early differentiation between Churg-Strauss syndrome and the hypereosinophilic syndrome increasingly clinically important. Patients with hypereosinophilic syndrome should be tested for the presence of the FIP1L1-PDGRFA-mutatition in order to identify patients that could benefit from a treatment with a tyrosine kinase inhibitor such as Imatinib. At present, immunosuppression is still the treatment of first choice for Churg-Strauss syndrome. Novel treatment modalities for both diseases include immunomodulation with interferon alpha and biologics such as antibodies against interleukin 5.