[Treatment of giant cell arteritis: what is in the pipeline?] / Therapie der Riesenzellarteriitis: Was ist in der Pipeline?

Glucocorticoids (GC) represent the standard treatment in remission induction and maintenance in the treatment of giant cell arteritis (GCA). Additive immunosuppressants are currently only recommended in special situations, such as refractory or relapsing disease or in cases of glucocorticoid-induced side effects. Methotrexate has been the standard steroid-sparing agent for many years. Meanwhile, tocilizumab is the first choice for steroid reduction, which was the first biological to be licensed for the treatment of GCA; however, long-term data over more than 3 years are lacking. A number of promising bDMARD and tsDMARD are currently being investigated in randomized controlled trials (RCT), which could contribute to additional effective steroid-sparing options in the treatment of GCA and help to establish an additive GC-sparing medication as the standard treatment in the future. This article gives an overview on current treatment studies for GCA.

EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis.

In this article, the 2009 European League Against Rheumatism (EULAR) recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been updated. The 2009 recommendations were on the management of primary small and medium vessel vasculitis. The 2015 update has been developed by an international task force representing EULAR, the European Renal Association and the European Vasculitis Society (EUVAS). The recommendations are based upon evidence from systematic literature reviews, as well as expert opinion where appropriate. The evidence presented was discussed and summarised by the experts in the course of a consensus-finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) determined. In addition to the voting by the task force members, the relevance of the recommendations was assessed by an online voting survey among members of EUVAS. Fifteen recommendations were developed, covering general aspects, such as attaining remission and the need for shared decision making between clinicians and patients. More specific items relate to starting immunosuppressive therapy in combination with glucocorticoids to induce remission, followed by a period of remission maintenance; for remission induction in life-threatening or organ-threatening AAV, cyclophosphamide and rituximab are considered to have similar efficacy; plasma exchange which is recommended, where licensed, in the setting of rapidly progressive renal failure or severe diffuse pulmonary haemorrhage. These recommendations are intended for use by healthcare professionals, doctors in specialist training, medical students, pharmaceutical industries and drug regulatory organisations.

[Clinical spectrum of IgG4-related diseases and the connection to rheumatology]. / Klinisches Spektrum der IgG-4-assoziierten Erkrankungen und der Bezug zur Rheumatologie.

Rheumatologist should be familiar with the concept of IgG4-related disease (IgG4-RD). Due to the clinical spectrum IgG4-RD can fall directly within the scope of rheumatology and are often diagnosed primarily by rheumatologists. Furthermore, IgG4RD are relevant differential diagnoses for many other rheumatic conditions. Finally, there are an increasing amount of data suggesting an important role of immunological processes observed in IgG4-RD for other rheumatic diseases.

[ANCA-associated vasculitis]. / ANCA-assoziierte Vaskulitiden.

The vasculitides represent one group of the systemic rheumatic diseases. Among the vasculitides we distinguish between large- (i.e. giant cell arteritis), medium- (i.e. polyarteritis nodosa) and small-vessel vasculitides (i.e. ANCA-associated vasculitides). Granulomatosis with polyangiitis, microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis belong to the ANCA-associated vasculitides. They share the features of vasculitic manifestations in small- to medium-sized vessel beds (which can occur in almost any organ system) and the presence of ANCA, the detection of which, however, is not necessarily mandatory. The treatment of AAV depends on disease stage and activity and is carried out on the basis of randomized controlled trials with an initial regimen aimed at inducing remission followed by maintenance treatment. In addition to glucocorticoids, conventional immunosuppressants (such as methotrexate, azathioprine and cyclophosphamide) form the basis of treatment, whereby rituximab, first licensed for the treatment of severe active GPA and MPA in 2013, has emerged as new treatment option.

Genetics of toll like receptor 9 in ANCA associated vasculitides.

OBJECTIVES: To investigate the contribution of genetic polymorphisms of toll like receptor (TLR) 9 and related genes on the susceptibility and clinical manifestation of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV). METHODS: Four single nucleotide polymorphisms (SNPs) in TLR9 were genotyped in 863 German AAV cases and 1344 healthy controls. Significant results were replicated in a cohort of 426 Dutch and British AAV cases. 11 polymorphisms in TLR9 related genes were studied concomitantly. RESULTS: A strong association of TLR9 genotypes and haplotypes with granulomatosis with polyangiitis was observed as well as a contrariwise association with microscopic polyangiitis. The association was confirmed when cases were compared according to ANCA status rather than to clinical entity. This was partly replicated in the second cohort leading to a striking overall difference in TLR9 allele/haplotype frequencies between proteinase 3 (PR3) ANCA+ and myeloperoxidase (MPO) ANCA+ cases (p=0.00000398, pc=0.000016, OR 1.68 (95% CI 1.35 to 2.1) for rs352140; p=0.000011, pc=0.000044, OR 1.64 (95% CI 1.31 to 2.04) for a 3-SNP haplotype). No significant association or epistatic effect was detected for TLR9 related genes: interleukin 6, interleukin 23 receptor, myeloid differentiation primary response 88, TNF receptor-associated factor 6, interleukin-1 receptor-associated kinase 4, discs large homolog 5 and nucleotide-binding oligomerisation domain containing 2. CONCLUSIONS: We provide further evidence that PR3-ANCA+ AAV differs genetically from MPO-ANCA+ AAV. TLR9 signalling may be involved in disease pathology, favouring models of infectious agents triggering AAV development.

[Genetic risk factors for vasculitis]. / Genetische Risikofaktoren von Vaskulitiden.

Among the vasculitides, genome-wide association studies (GWAS) have so far been performed for Behçet's disease, Kawasaki disease, granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). These studies delivered valuable information with respect to the pathogenesis and therapeutic targets: Apart from HLA-B51 and HLA-A26, distinct polymorphisms in cytokine (IL-10) or cytokine receptor (IL-12R/IL-23R) genes, transcription factors (STAT4) and genes encoding for proteins involved in antigen presentation (ERAP-1) have been identified as risk factors for Behçet's disease. The results of two GWAS performed for antineutrophil cytoplasmic antibody (ANCA) associated vasculitis GPA and MPA in Europe and the USA confirmed that the HLA-DP locus is the most relevant risk factor for GPA. Furthermore, the European GWAS confirmed SERPINA-1, a deficiency allele of the α-1-antitrypsin gene, as a genetic risk factor in GPA and identified a polymorphism in the proteinase 3 gene (PR3), one of the target antigens of ANCA, as a risk factor for GPA and PR3-ANCA-associated vasculitis.

[ANCA-associated vasculitis]. / ANCA ("anti-neutrophil cytoplasm antibody")-assoziierte Vaskulitiden.

Granulomatosis with polyangiitis, microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis belong to the anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitides (AAV). They share the feature of vasculitic manifestations in small to medium-size vessel beds which can occur in nearly any organ system. The treatment of AAV is dependent on stage and activity and is carried out on the basis of randomized controlled trials with an initial remission induction regimen followed by maintenance treatment. Apart from glucocorticoids, conventional immunosuppressants are the basis of treatment whereby biologics, such as rituximab have emerged as new treatment options.

[Update on granulomatosis with polyangitis (GPA, Wegener's granulomatosis)]. / Update Granulomatose mit Polyangiitis (GPA, Wegener-Granulomatose).

Granulomatosis with polyangitis (GPA, Wegener's granulomatosis) is characterized by a granulomatous inflammation of the respiratory tract and a necrotizing ANCA-associated small to medium-size vessel vasculitis with a predilection for the lungs (pulmonary capillaritis) and kidneys (necrotizing glomerulonephritis). The disease evolves stage-wise and typically starts as inflammation of the respiratory tract followed by development of systemic vasculitis manifestations. Today, treatment is evidence-based and adapted according to activity and disease stage which has resulted in a significant improvement in long-term outcome. Early mortality during the first year of treatment poses one of the main problems and is a result of infections under immunosuppressive treatment. Furthermore, treatment of refractory disease activity which is often represented by granulomatous manifestations is still a challenge and may result in significant organ damage if not treated successfully.

[Neurological manifestations of vasculitis and primary central nervous system vasculitis]. / Neurologische Manifestationen von Vaskulitiden und primäre ZNS-Vaskulitis.

Neurologic complications of vasculitis occur frequently in the form of either peripheral neuropathy or manifestations within the central nervous system (CNS). Primary vasculitis of the CNS is characterized by central nervous system manifestations only with no evidence of systemic disease manifestations. Large vessel vasculitis is particularly associated with central nervous system complications, such as ischemic cerebral infarcts whereas medium size, e.g. polyarteritis nodosa and small vessel vasculitis, e.g. antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis manifest with peripheral neuropathies and central nervous system complications. The same also holds true for Behçet's disease which affects both large, medium and small sized arteries and veins. Due to the severity of nervous system manifestations a highly potent immunosuppressive therapy (e.g. cyclophosphamide and glucocorticoids) is usually required for remission induction. Virus-associated vasculitis (e.g. hepatitis C-associated cryoglobulinemic vasculitis) should receive antiviral therapy as first line treatment. Chronic damage is frequent in spite of swift initiation of immunosuppressive treatment.

ANCA-associated vasculitis is linked to carriage of the Z allele of α1 antitrypsin and its polymers.

BACKGROUND: Small studies have linked α1 antitrypsin (α1AT) deficiency to patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). OBJECTIVE: To test the validity and the mechanism of this association between α1AT and AAV. METHODS: The distribution of α1AT deficiency alleles Z and S was compared between 856 White Europeans with AAV and 1505 geographic and ethnically matched healthy controls. Genotyping was performed by allelic discrimination assay. RESULTS: were compared between cases and controls using χ(2) tests. The serum and renal biopsies for α1AT polymers were compared using the polymer-specific 2C1 antibody. The role of α1AT polymers in promoting inflammation was investigated by examining their ability to prime neutrophils for ANCA activation as assessed by CD62L shedding, superoxide production and myeloperoxidase degranulation. Results The Z but not the S allele was over-represented in the patients compared with controls (HR=2.25, 95% CI 1.60 to 3.19). Higher concentrations of polymers of α1AT were detected in serum from patients carrying the Z allele than in those not carrying the Z allele (median (IQR) 1.40 (0.91-3.32) mg/dl vs 0.17 (0.06-0.28) mg/dl, p<0.001); polymers of α1AT were also seen in the renal biopsy of a patient with vasculitic glomerulonephritis. Polymers of α1AT primed neutrophils with CD62L shedding and increased superoxide production following ANCA activation. Carriage of the Z allele was not associated with disease severity, survival or relapse. CONCLUSIONS: The Z but not the S deficiency allele is associated with AAV. Polymers of α1AT are present in the serum and glomeruli of at least some patients with the Z allele, which may promote inflammation through priming of neutrophils.

[The genetics of vasculitides]. / Genetischer Hintergrund der Vaskulitiden.

Genetic association studies have been of great value in the past by contributing to the understanding of pathophysiological mechanisms of chronic inflammatory and autoimmune diseases. Many genetic risk factors have been identified which confer susceptibility for one or several (autoimmune) disease(s). Using a candidate-gene approach, the first genetic risk factors and polymorphisms of vasculitides have been identified. Due to the rarity of autoimmune vasculitides often only small sample numbers have been generated and analysed, leading to inconsistent results. Furthermore, differences in ethnic background may complicate analysis. Only few of the detected risk factors have been reliably replicated in larger cohorts, such as the association of the PTPN22*620W allele with WG and MPA, the deficiency allele Pi*Z of the alpha1 antitrypsin gene and the HLA-DPB*04041 allele with WG and the HLA-DRB3/DRB4 with CSS. Genome-wide association studies (GWAS) offer the advantage of screening the whole genome for risk factors rather than relying on disease models postulated by the investigator; however, they require even larger sample sizes. Initial results from GWA studies are available for Behçet's disease and Kawasaki syndrome, which identified new genetic associations but require replication, especially since some of the identified risk factors could not be linked to pathophysiological pathways to date.

[Therapy of vasculitides: according to recommendations of the European League Against Rheumatism (EULAR) and European Vasculitis Study Group (EUVAS)]. / Therapiestrategien bei Vaskulitiden: Entsprechend den Empfehlungen der European League Against Rheumatism (EULAR) und der European Vasculitis Study Group (EUVAS).

The stringent definition of disease and activity stage as well as the performance of several controlled trials in the field of vasculitis in the past years now enables an evidence-based stage and activity adapted treatment, especially for ANCA-associated vasculitides. On the basis of available controlled trials, the European League Against Rheumatism (EULAR) and European Vasculitis Study Group (EUVAS) established and published recommendations for the management of vasculitides. This manuscript summarizes the treatment recommendations published in 2009 and highlights new studies which have been published since then.

[Classification and therapy of vasculitis according to recommendations of the European League Against Rheumatism (EULAR)]. / Klassifikation und leitliniengerechte Empfehlungen zur Diagnose und Therapie von Vaskulitiden.

Vasculitis is still being classified according the criteria of the American College of Rheumatology and the Chapel Hill Consensus Conference Definitions. Diagnostic criteria are currently being established. The classification criteria are based on the size of the inflamed blood vessel (e.g. large vessel vasculitis with inflammation of the aorta and its branches), clinical symptoms and findings (such as cephalalgia in giant cell arteritis) and histological findings. In recent years a definition of disease stages and activity has been established and a number of controlled trials have been carried out in order to provide evidence-based stage and activity adapted therapy regimens. Recommendations for the management of vasculitis have been published in 2009 by EULAR (European League Against Rheumatism). This article gives a review of the classification of vasculitis and summarizes the current European guidelines on management.

[Pulmonary fibrosis]. / Lungenfibrose.

Many, different diseases can result in pulmonary fibrosis and its prevalence is continuously increasing. Pulmonary fibrosis is defined by a diffuse accumulation of connective tissue in the interstitial space resulting in destruction of lung parenchyma. Older individuals are more often affected by this disease than younger. Approximately one half of all patients with pulmonary fibrosis suffer from rheumatic diseases. The classification of pulmonary fibrosis was revised 1998. Now 6 different types of interstitial pneumonia according to 6 different pathologic patterns are newly defined. Still, there is no efficient treatment known, which resolves fibrotic lung remodeling. However, immunosuppressive treatment strategies are established in pulmonary fibrosis evoked by inflammatory processes.

Novel association of the CD226 (DNAM-1) Gly307Ser polymorphism in Wegener's granulomatosis and confirmation for multiple sclerosis in German patients.

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).

ANCA-associated vasculitides: pathogenetic aspects and current evidence-based therapy.

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.

[Autoimmune vasculitides. Standards and guidelines of EULAR and EUVAS]. / Autoimmunvaskulitiden: Standards und Leitlinien nach EULAR und EUVAS.

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.