[Vasculitis mimics]. / Vaskulitis-Mimics.

Vasculitis mimics need to be differentiated from primary and secondary vasculitides as described in the Chapel Hill nomenclature. The clinical symptomatology resembles that of vasculitis of small and medium, rarely also large vessels and hence imitates the classical vasculitic disorders. Pathogenetically, the causes are partly genetic mutations, embolization syndromes, infections and substance abuse. Also, B­cell lymphomas can mimic vasculitis. The present manuscript summarizes the vasculitis mimics.

[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.

[Development of morbidity and mortality in ANCA-associated vasculitis]. / Entwicklung von Morbidität und Mortalität bei ANCA-assoziierten Vaskulitiden.

The outcome of ANCA (antineutrophil cytoplasmic antibody)-associated vasculitis (AAV) has been significantly improved due to the combined use of cyclophosphamide (CYC) and glucocorticosteroids. Recent studies demonstrated a normalization of life expectancy for several subgroups of AAV patients. Mortality is highest in the first year after diagnosis and infections are the most frequent cause of death. Older age and renal failure are associated with worse outcome. The use of Pneumocystis jiroveci prophylaxis and subsequent activity-adapted GC dose reduction (target: below 10 mg per day) can substantially reduce the risk of severe infections. Late sequelae of CYC medication, such as cystitis and malignancy should be recognized and can be minimized by the usage of uroprotection with mesna and avoidance of high cumulative CYC doses.

Use of methotrexate in ANCA-associated vasculitides.

Since the introduction of combined immunosuppressive therapy consisting of oral cyclophosphamide (CYC) and glucocorticosteroids (GC) in the 1970s, the outcome of antineutrophil cystoplasmic antibodies (ANCA)-associated vasculitides has improved dramatically over the last decades. However, the long-term follow-up of patients treated with CYC plus GC has revealed a high treatment-related morbidity and mortality and a high proportion of patients suffering from relapses (up to 50%), requiring CYC and GC again. Methotrexate (MTX) can replace CYC for induction of remission in patients with a non life-threatening disease course of ANCA associated vasculitides ('early systemic'). Furthermore, MTX can be used as a maintenance medication after induction of remission with CYC (plus GC), provided there is a decent renal function with a GFR >50 ml /min. As with any maintenance regimen, we do not know exactly for how long to continue MTX maintenance therapy. When using MTX as remission induction or maintenance regimen a tight control of urinary sediment and kidney function is mandatory in order to detect a potential renal relapse or de novo manifestation.

[Cyclophosphamide versus bolus in Wegener's granulomatosis and other ANCA-related vasculitides: advantages and disadvantages]. / Cyclophosphamid oral vs. Bolus bei Wegener-Granulomatose und anderen ANCA-assoziierten Vaskulitiden: Pro und Contra.

Cyclophosphamide remains the therapy of choice in severe ANCA positive vasculitis. In order to avoid the considerable side effects of high cumulative doses sometimes manifesting themselves years later, induction therapy with a low cyclophosphamide dose and an early switch to cyclophosphamide-free maintenance regimens should be aimed for. This can be achieved by an induction therapy of 3--6 months of intravenous pulse therapy (pCYC) or oral therapy (oCYC). The metaanalysis of therapeutic trials in ANCA vasculitis demonstrates a slightly higher induction rate of remission, but an increased relapse rate of pCYC compared to oCYC. The incidence of adverse events seems to be higher in oCYC compared to pCYC. The results of the first controlled prospective multicenter trial (CYCLOPS) directly comparing pCYC and oCYC treatment of ANCA-positive vasculitis are eagerly awaited. It will be important to extend the follow-up over several years in order to reach a valid estimate of the incidence of secondary malignancies due to CYC therapy.

[Wegener's granulomatosis and microscopic polyangiitis]. / Wegener-Granulomatose und mikroskopische Polyangiitis.

Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) are primary systemic small vessel vasculitides, associated with a positive C/PR3-ANCA in WG and P/MPO-ANCA in MPA. The most prominently involved organs are the upper (only in WG) and lower respiratory tract and the kidneys. The diagnostic work-up is an interdisciplinary approach assessing disease stage and extent. Treatment is adapted to disease stage and extent and relies on a combination of a cytotoxic plus a tapering regimen of corticosteroids. Induction of remission in "early systemic" disease can be achieved with low-dose methotrexate. In severe generalized vasculitis cyclophosphamide (CYC) is the mainstay of therapy, in rapidly progressive glomerulonephritis in combination with plasmapheresis. After 3-6 months of induction CYC is switched to a maintenance treatment with azathioprine. Alternatives are leflunomide, mycophenolate or methotrexate (creatinine < 150 micromol/l). Age > or = 50 at diagnosis, renal dysfunction and pulmonary involvement are associated with higher mortality rates. The relapse rate is approximately 50% within 5 years, being higher in WG than MPA.

Standardized neurologic evaluations of 128 patients with Wegener granulomatosis.

OBJECTIVE: To assess the frequency and type of neurologic involvement in a cohort of patients with generalized Wegener granulomatosis (WG). PATIENTS AND METHODS: In a prospective analysis the clinical, electrophysiologic, radiological, and serologic data of 128 patients have been studied over a median observation period of 19 months (range, 1-60 months). RESULTS: Sixty-four patients (50%) revealed central or peripheral nervous system involvement. Peripheral neuropathy (PN) affected 56 patients, in 9 cases the central nervous system was involved, and in 6 cases the cranial nerves were involved. Thirty-one patients showed a distal symmetrical polyneuropathy, 25 a mononeuritis multiplex. Within the first 2 years of the disease course 47 of the 56 patients had developed their PN, sometimes as the initial symptom of WG. Patients with PN were significantly more often male (34 of 65 patients) than female (22 of 63 patients, P =.04), were significantly older at the onset of WG (median age, 53 vs 44 years; P =.001), had a significantly larger disease extent (P =.001), and had higher classic antineutrophil cytoplasmic antibody titers (P =.002) than neurologically unaffected patients. Response to immunosuppression was moderate concerning peripheral nervous system manifestations. CONCLUSIONS: Peripheral neuropathy is frequent in generalized WG, occurring early in the disease course. As PN can be the first and sole symptom of a beginning systemic vasculitis, it is important that in cases of PN of an unclear origin, interdisciplinary investigations are initiated to detect, treat, and closely follow-up a possible underlying WG, especially as these patients seem to have a more severe disease course.

Response to trimethoprim/sulfamethoxazole in Wegener's granulomatosis depends on the phase of disease.

We prospectively studied trimethoprim/sulfamethoxazole (T/S) in inducing remission in 'initial phase' Wegener's granulomatosis (WG), and in sustaining remission in generalized WG, in 72 patients in various disease stages. Nineteen patients with initial phase WG received T/S (2 x 960 mg/day). Another 24 patients with generalized WG received the same dose of T/S (group A) and were compared with 21 patients receiving no further treatment after standard therapy (group B). Eight patients were given T/S plus low-dose prednisone (group C). Eleven of 19 patients (58%) with initial phase WG achieved complete or partial remission lasting a median 43 months (range 6-88 months). Of the remaining eight (42%), five showed local disease progression, and three developed generalized WG. In group A (T/S alone, generalized WG), 10/24 (42%) suffered a relapse after a median 13 months (range 4-58 months). In group B (generalized WG, no further treatment) 29% of patients relapsed after a median 22.5 months (range 18-26 months). All eight patients treated with T/S plus low-dose prednisone (group C) suffered serious relapse after 2-24 months. T/S induced long-term remission in > 50% of patients with initial phase WG; however, neither T/S alone nor T/S plus low-dose prednisone sustained remission in generalized WG.

ANCA against the bactericidal/permeability increasing protein (BPI-ANCA) can compromise the antibiotic function of BPI in a Wegener's granulomatosis patient.

A 54-year old Wegener's granulomatosis patient with PR3-ANCA at diagnosis 2 years ago was admitted with a pulmonary relapse and new subglottic stenosis preceded by pulmonary infections. The patient presented with bactericidal/permeability increasing protein (BPI)-ANCA in ELISA whereas at the same time PR3-ANCA had disappeared. Bronchoalveolar lavage revealed pulmonary infection with Gram-negative bacteria. After antibiotic treatment, immunosuppression was started with cyclophosphamide and infliximab due to refractory disease. Remission was induced and BPI-ANCA disappeared. A bacterial growth inhibition assay with BPI and the patient's IgG purified during the actual pulmonary relapse showed inhibition of the antimicrobial activity of BPI in vitro, in contrast to IgG from sera taken 2 years before and after remission was induced. The patient's BPI-ANCA recognised the bioactive N-terminal portion of BPI. Thus a possible mechanism is demonstrated for how BPI-ANCA may contribute to a pro-inflammatory setting during the development of a pulmonary relapse in the absence of PR3-ANCA by impeding bacterial clearance.

Severe CNS manifestations as the clinical hallmark in generalized Wegener's granulomatosis consistently negative for antineutrophil cytoplasmic antibodies (ANCA). A report of 3 cases and a review of the literature.

OBJECTIVE: Antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 are highly specific for Wegener's granulomatosis (WG); their sensitivity for active generalized WG is nearly 100%. There are patients, however, who fulfill both the ACR 1990 criteria and the CHC 1992 definition for WG but who remain ANCA negative. The authors report 3 young patients with biopsy-proven active generalized WG who were consistently negative for ANCA over observation times ranging from 58 to 114 months. METHODS: ANCA titers were determined serially every 3 months. ANCA-negativity was defined by the absence of any fluorescence pattern on IFT plus the absence of any specific ELISA reactions. This included negative results for the antibody classes IgG, IgM and IgA. The sera of all patients were also tested in a capture PR3-ANCA ELISA. At 1- to 6-month intervals each patient underwent a standardized set of interdisciplinary examinations. RESULTS: Although CNS involvement in large WG cohorts is about 10%, severe CNS manifestations were the clinical hallmark in all 3 patients. One patient suffered from both intraspinal and intracerebral disease with fatal outcome; the other 2 had meningeal manifestations that responded favorably to immunosuppressive therapy. CONCLUSION: Severe CNS manifestations could represent a clinical hallmark of patients with generalized Wegener's granulomatosis who are consistently negative for antineutrophil cytoplasmic antibodies (ANCA).

Development and validation of a disease extent index for Wegener's granulomatosis.

AIMS: The quantitative assessment of disease extent (staging) and activity (grading) in patients with ANCA-associated vasculitides is one prerequisite for the comparison of outcomes in different patient cohorts. We present a validation study of the Disease Extent Index (DEI). METHODS: 66 patients with Wegener's granulomatosis were examined to assess the validity, reliability and sensitivity to change of the DEI. Correlation coefficients were calculated to estimate associations between DEI and BVAS (Birmingham Vasculitis Activity Score), a previously established activity score, and between DEI and serological markers. RESULTS: Among patients with active disease, DEI correlated significantly with cANCA titer (r = 0.46), leukocyte count (r = 0.38) and platelet count (r = 0.53). Among patients in remission, DEI correlated significantly with cANCA titer (r = 0.61), CRP (r = 0.47) and sIL2R (r = 0.47). Additionally, a high association of DEI and BVAS (r = 0.9) confirmed a rather high convergent validity. The effect size of DEI equals 2.37 standard deviation units and indicates a considerable change from active disease to remission. CONCLUSIONS: The DEI is valid, reliable, easy, quick to perform and highly reproducible. Although it correlates with some surrogate markers of disease activity and the BVAS, the DEI quantifies different domains of the disease than the BVAS and should therefore be used in conjunction with the BVAS.

[Radiology of the primary systemic vasculitides]. / Radiologie der primären systemischen Vaskulitiden.

Determination of disease extension and disease activity are in the foreground of diagnostic imaging in vasculitides. There are several radiologic modalities available each having specific indications. Magnetic resonance imaging (MRI) readily depicts granulomas and mucosal inflammations in the paranasal sinuses, nasal cavity and orbits. Computed tomography detects osseous lesions of the skull. Due to its superb sensitivity MRI is an established screening modality for CNS vasculitides, although there are limitations with regard to specificity. In spite of its limited accuracy in most institutions angiography is still required for radiological confirmation of CNS vasculitis. Perfusion and diffusion MR-imaging may combine the advantages of "conventional" MRI and angiography. By now the method is not fully validated for vasculitides, however. Vascular disease in Takayasu's arteritis and in giant cell arteritis involving predominantly large and medium sized vessels is readily diagnosed by non invasive magnetic resonance angiography. Percutaneous transluminal angioplasty has proven to be an effective and save therapeutic modality for the cure of vascular stenoses and occlusions. Plain film radiography in two planes is the established modality for pulmonary imaging. In pulmonary vasculitides a more thorough analysis of lung disease is provided by high resolution computed tomography. Diagnostic imaging does substantially assist in the interdisciplinary management of patients suffering from vasculitides.

[Inflammatory aortic arch syndrome: contrast-enhanced, three-dimensional MR angiography in stenotic lesions]. / Entzündliches Aortenbogensyndrom: Stenosediagnostik mittels kontrastmittelverstärkter 3D-MR-Angiographie im Vergleich mit der DSA.

PURPOSE: To determine the value of contrast-enhanced, three-dimensional MR angiography for the evaluation of stenotic and occlusive vascular lesions in inflammatory aortic arch syndrome. MATERIALS AND METHODS: 14 patients with inflammatory aortic arch syndrome (giant cell arteritis: n = 8, Takayasu arteritis: n = 4, ankylosing spondylitis: n = 1 sarcoidosis: n = 1) underwent MR angiography of the aortic arch and the supra-aortic vessels (n = 15, 2 patients were examined twice) and of the abdominal aorta (n = 2). MRA was performed using a 3D-FLASH sequence (TR/TE 4.6/1.8 ms, flip angle 30 (3)) on a 1.5T system. MRA imaging was compared with the findings of DSA, which served as gold standard. RESULTS: In a total of 467 examined vascular territories, DSA revealed 50 stenoses and 35 occlusions. All lesions were detected by MRA. In 23 segments, the degree of stenosis was overestimated by MRA. Sensitivity and specificity of MRA were 100 % and 94.3 %, positive and negative predictive values were 73.6 and 100 %, and the accuracy was 95.1 %. CONCLUSIONS: Despite a tendency to overestimate stenoses, contrast-enhanced three-dimensional MR angiography is a valid, non-invasive technique in the assessment of inflammatory aortic arch syndrome.

Effectiveness of cyclophosphamide pulse treatment in Wegener's granulomatosis.

43 patients with Wegener's granulomatosis were studied to evaluate the effectiveness of cyclophosphamide (cyc) pulse treatment. 42% of the patients showed benefits from treatment for at least 6 months after the cessation of cyc pulses. Analysis of clinical and laboratory parameters indicate that this treatment is less effective in patients in whom more than 4 organ systems are involved. Responders to the treatment showed disease manifestations predominantly in the ENT and lower respiratory tract and had lower cANCA titers (< 1:64) prior to treatment.

Treatment of Wegener's granulomatosis with intravenous immunoglobulin.

We report about the treatment of eight patients with Wegener's granulomatosis and one patient with systemic pANCA-associated vasculitis with a single course of high-dose intravenous immunoglobulin (IVIG). In 5 of 9 patients (55%) this resulted in significant clinical improvement, in two patients a decrease of the ANCA-titre was seen.

Treatment of Wegener's granulomatosis.

Treatment and outcome of 111 patients who fell ill with Wegener's granulomatosis (WG) between 1966 and 1990 were analysed retrospectively. Two regimens of treatment were distinguished: "conventional" treatment, i.e. daily application of cyclophosphamide/corticosteroids (FAUCI scheme) or azathioprine/corticosteroids or corticosteroids alone, and "stage-adapted" treatment, characterized by change of different treatments (e.g. cyclophosphamide pulse therapy, cotrimoxazole) according to the extent and activity of disease. In patients who received stage-adapted treatment, exacerbations occurred significantly more frequent than in conventionally treated patients, while lethal outcome was much more frequent in conventionally treated patients.