[The unusual mimicker of a polymyositis]. / Der außergewöhnliche Nachahmer einer Polymyositis.

This article describes a hantavirus-associated pronounced myositis as a rare differential diagnosis to polymyositis. The literature on the pathogenesis of hantavirus disease discusses less a direct viral cytopathology but more a secondary immune dysregulation with induction of a capillary leak. This article describes for the first time a case of successful treatment of protracted hantavirus myositis using high-dose glucocorticoids and cyclophosphamide, followed by ciclosporin and MTX.

[Pathogenesis of large vessel vasculitides]. / Pathogenese der Großgefäßvaskulitiden.

Large vessel vasculitides comprise two distinct entities, giant cell arteritis (GCA) and Takayasu arteritis (TAK). GCA is the most common vasculitis in central Europe, becoming manifested at an age over 50 years. In contrast, the much rarer TAK affects almost exclusively young adults and mostly women. Both vasculitides are granulomatous arteritides affecting mainly the aorta and its major arterial branches. GCA and TAK are associated with different major histocompatibility complex genes. Infections possibly play a role in the initiation of large vessel vasculitides. Activation of dendritic cells in the adventitia induces chemokine and cytokine-mediated recruitment and maturation of T­helper (Th)1 and Th17 cells and macrophages producing cytokines, growth factors and matrix metalloproteinases. In GCA, CD4+ T­helper cells and macrophages are predominantly found in the inflammatory infiltrate. In TAK, the infiltrate also contains cytotoxic CD8+ T­cells and γδ T­cells. This could indicate different antigenic triggers in GCA and TAK. Inflammatory infiltration with T­cells and macrophages and activation of myofibroblasts and smooth muscular cells induce vascular remodeling with intimal hyperplasia and destruction of the media. Remodeling is histologically characterized by progressive arterial wall fibrosis, vascular stenosis and obstruction. In summary, GCA and TAK represent two different entities with a distinct human leukocyte antigen (HLA) and potentially etiopathogenetic background. Clinically, inflammation-related general symptoms and signs of ischemia are encountered, accompanied by increased levels of serological markers of inflammation.

[De-escalation of therapy in ANCA-associated vasculitides]. / Therapiedeeskalation bei ANCA-assoziierten Vaskulitiden.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) require a differentiated therapeutic approach depending on the degree of organ dysfunction and disease activity. In organ dysfunction and life-threatening AAV cyclophosphamide and rituximab are recommended for the induction of remission. For remission induction with a lack of organ dysfunction and non-life-threatening AAV, methotrexate or mycophenolate mofetil are recommended. For remission maintenance therapy azathioprine or methotrexate are used. In the case of contraindications, intolerance or previous failure of azathioprine and methotrexate treatment, rituximab, leflunomide or mycophenolate mofetil may be used as alternatives. Maintenance therapy is usually continued for at least 2 years. De-escalation of therapy requires continuous clinical monitoring while the glucocorticoid medication and immunosuppressive therapy is tapered; however, every de-escalation of therapy carries a risk of relapse.

Effector memory T­cells in the pathogenesis of ANCA-associated vasculitides.

Patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) have an expansion of effector memory T­cells in peripheral blood. The enlarged effector memory cell population contains distinct cell subsets, including T­helper type 1 (Th1) CD4+ T­cells lacking co-stimulatory CD28 expression and Th17 cells in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) and Th2 type and Th17 cells in eosinophilic granulomatosis with polyangiitis (EGPA). The cytokine response of autoreactive proteinase 3 (PR3)-specific effector memory T­cells is skewed towards an increase of Th2 type, Th17, and Th22 cell fractions in GPA. Anomalous effector memory CD4+ T­cell co-stimulation is suggested by the aberrant expression of P­selectin glycoprotein ligand-1, ß­2 integrin, chemokine receptors, natural-killer group 2 member D (NKG2D) and other activating receptors. The increased expression of these receptors is accompanied by T­cell activation and migration to inflamed tissues. T­cells are abundant and secrete proinflammatory cytokines in inflammatory lesions in AAV. The T­cell mediated tissue damage correlates with renal outcome, whereas B­cell infiltration does not. Activation of lesional CD4+NKG2D+ effector memory T­cells is independent of the antigen; moreover, CD4+NKG2D+ effector memory T­cells display NK-cell-like cytotoxicity towards microvascular endothelial cells in vitro. Thus, effector memory T­cells play an important role in tissue damage and disease progression in AAV. Sequentially administered or combined with B­cell depleting therapy, T­cell-directed therapies, especially those directed against effector memory CD4+ T­cells, may further improve the outcome and help to achieve long-term remissions in AAV.

[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.

[Effector memory T­cells in the pathogenesis of ANCA-associated vasculitides. German version]. / Effektor-Memory-T­Zellen in der Pathogenese von ANCA-assoziierten Vaskulitiden.

Patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) have an expansion of effector memory T­cells in peripheral blood. The enlarged effector memory cell population contains distinct cell subsets, including T­helper type 1 (Th1) CD4+ T­cells lacking co-stimulatory CD28 expression and Th17 cells in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) and Th2 type and Th17 cells in eosinophilic granulomatosis with polyangiitis (EGPA). The cytokine response of autoreactive proteinase 3 (PR3)-specific effector memory T­cells is skewed towards an increase of Th2 type, Th17 and Th22 cell fractions in GPA. Anomalous effector memory CD4+ T­cell co-stimulation is suggested by the aberrant expression of P­selectin glycoprotein ligand­1, beta­2 integrin, chemokine receptors, natural-killer group 2 member D (NKG2D) and other activating receptors. The increased expression of these receptors is accompanied by T­cell activation and migration to inflamed tissues. The T­cells are abundant and secrete proinflammatory cytokines in inflammatory lesions in AAV. The T­cell mediated tissue damage correlates with renal outcome, whereas B-cell infiltration does not. Activation of lesional CD4+NKG2D+ effector memory T­cells is independent of the antigen; moreover, CD4+NKG2D+ effector memory T­cells display NK-cell-like cytotoxicity towards microvascular endothelial cells in vitro. Thus, effector memory T­cells play an important role in tissue damage and disease progression in AAV. Sequentially administered or combined with B-cell depleting therapy, T­cell-directed therapies, especially those directed against effector memory CD4+ T­cells, may further improve the outcome and help to achieve long-term remission in AAV.

Preliminary classification criteria for the cryoglobulinaemic vasculitis.

BACKGROUND: To develop preliminary classification criteria for the cryoglobulinaemic syndrome or cryoglobulinaemic vasculitis (CV). METHODS: Study part I developed a questionnaire for CV to be included in the formal, second part (study part II). Positivity of serum cryoglobulins was defined by experts as an essential condition for CV classification. In study part II, a core set of classification items (questionnaire, clinical and laboratory items, as agreed) was tested in three groups of patients and controls-that is, group A (new patients with the CV), group B (controls with serum cryoglobulins but lacking CV) and group C (controls without serum cryoglobulins but with features which can be observed in CV). RESULTS: In study part I (188 cases, 284 controls), a positive response to at least two of three selected questions showed a sensitivity of 81.9% and a specificity of 83.5% for CV. This questionnaire was employed and validated in study part II, which included 272 patients in group A and 228 controls in group B. The final classification criteria for CV, by pooling data from group A and group B, required the positivity of questionnaire plus clinical, questionnaire plus laboratory, or clinical plus laboratory items, or all the three, providing a sensitivity of 88.5% and a specificity of 93.6% for CV. By comparing data in group A versus group C (425 controls), the same classification criteria showed a sensitivity 88.5% and a specificity 97.0% for CV. CONCLUSION: Classification criteria for CV were developed, and now need validation.

[T-cells in ANCA-associated vasculitis]. / T-Zellen bei ANCA-assoziierten Vaskulitiden.

CD4+NKG2D+effector memory T-cell-mediated endothelial cell damage and a Th17 dominated cytokine profile of PR3-specific T-cells may play an important role in the pathogenesis of granulomatosis with polyangiitis (Wegener's). The anti-IL-5 antibody mepolizumab (anti-IL-5) induces remission in Churg-Strauss syndrome.

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).

Severe impaired respiratory ciliary function in Wegener granulomatosis.

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.

Olfactory dysfunction in Wegener's granulomatosis.

Necrotizing granulomatous inflammation of the upper respiratory tract is one of the hallmarks of Wegener's granulomatosis (WG), which may explain the reason for olfactory dysfunction in WG. However, a systematic analysis using modem olfactory testing tools has not been performed and potential causes of dysfunction at different levels of olfactory information processing remain obscure so far. In this study a group of 76 WG-patients was examined with sniffin'sticks screening 12, odour threshold (T)/discrimination (D)/identification (I) TDI-score, active anterior rhinomanometry and a standardized questionnaire for olfactory function. WG-patients were aware of their olfactory dysfunction, as proven by psychophysiological test results. An altered olfactory function was significantly correlated to local administration of mupirocin and to the time interval between first diagnosis and study entry. None of the other variables had a statistical significant effect on the olfactory dysfunction.

[Adult-onset Still's disease, Schnitzler syndrome, and autoinflammatory syndromes in adulthood]. / Adulter Morbus Still, Schnitzler-Syndrom und autoinflammatorische Syndrome im Erwachsenenalter.

Adult-onset Still's disease (AoSD), Schnitzler syndrome, and cases of adult-onset autoinflammatory syndromes [10-15% of cases of familial Mediterranean fever (FMF) and tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS)] are characterized by a genetic predisposition, with increased interleukin (IL)-1beta and IL-18 production and TNF-alpha signaling, respectively. As a result, periodic fever and inflammation at barrier tissues (synovial tissues, serous membranes, and the skin) are encountered in such patients. Pathophysiological insights into these diseases have renewed interest in research on IL-1beta in rheumatic diseases and have opened new therapeutic avenues. Recently published studies have shown that patients with Schnitzler syndrome, methotrexate-refractory AoSD, and colchicine-refractory FMF or contraindications to colchicines in FMF respond well to treatment with the soluble IL-1 receptor antagonist anakinra. For TRAPS patients, the p75 TNF-alpha receptor/Fc-IgG1 fusion protein etanercept is the treatment of first choice.

[New pathogenetic aspects in primary systemic vasculitides]. / Neues zur Pathogenese primär systemischer Immunvaskulitiden.

Primary systemic vasculitides are defined according immunopathological features and the size of the involved vessels. Three anti-neutrophil cytoplasmic autoantibody (ANCA) associated small vessel vasculitides (Wegener's granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis) can be distinguished from the so-called Non-ANCA-associated vasculitides, i.e. granulomatous vasculitides of large vessels (giant cell arteritis, Takayasu arteritis) and immune complex-mediated vasculitides of medium-sized and small vessels (Polyarteriitis nodosa, Kawasaki disease and Henoch-Schönlein purpura, cryoglobulinemic vasculitis, cutaneous leukocytoklastische angiitis). Predisposing genetic and other endogenous and exogenous factors facilitate the activation of innate immunity and induce persisting inflammatory reactions resulting in different forms of (auto)-immune vasculitides.

[Autoinflammatory syndromes]. / Autoinflammatorische Syndrome.

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.