Rituximab in routine care of severe active rheumatoid arthritis : A prospective, non-interventional study in Germany.

OBJECTIVE: To assess safety, effectiveness and onset of effect of rituximab (RTX) in routine clinical treatment of severe, active rheumatoid arthritis (RA). METHODS: Prospective, multi-centre, non-interventional study in rheumatological outpatient clinics or private practices in Germany. RTX-naïve adult patients were to receive RTX according to marketing authorisation and at their physician's discretion. Also according to their physician's discretion, patients could receive a second cycle of RTX (re-treatment = treatment continuation). Major outcome was the change in Disease Activity Score based on 28-joints count and erythrocyte sedimentation rate (DAS28-ESR) over 24 weeks and during 6 months of re-treatment. RESULTS: Overall, 1653 patients received at least one cycle RTX; 99.2% of these had received disease-modifying antirheumatic drugs (DMARD) pre-treatment and 75.5% anti-tumor necrosis factor(TNF)­α pre-treatment. After a mean interval of 8.0 months, 820 patients received RTX re-treatment. Mean DAS28-ESR decreased from 5.3 at baseline to 3.8 after 24 weeks (-1.5 [95% confidence interval, CI: -1.6; -1.4]), and from 4.1 at start of cycle 2 to 3.5 at study end (change from baseline: -1.8 [95% CI: -2.0; -1.7]). Improvements in DAS28-ESR and Health Assessment Questionnaire (HAQ) score occurred mainly during the first 12 weeks of RTX treatment, with further DAS28-ESR improvement until week 24 or month 6 of re-treatment. Improvements in DAS28-ESR and EULAR responses were more pronounced in seropositive patients. RF was a predictor of DAS28-ESR change to study end. Safety analysis showed the established profile of RTX. CONCLUSION: RTX was safe and effective in a real-life setting with rapid and sustained improvement in RA signs and symptoms.

[Vasculitis. Treatment outcome parameters]. / Vaskulitis. Zielkriterien der Behandlung.

The definition of outcome parameters has improved the care of vasculitis patients dramatically in recent decades. In the first phase of joint European studies, disease stages and activity were defined. In the second and third phases results of the randomized and controlled trials were summarized and published as European recommendations for the care of small and large vessel vasculitis. Irrespective of the type of vasculitis, inducing remission, maintaining remission and preventing disease- and therapy-related complications are the main outcome criteria.

[Report on the 34th meeting of the German Clinical Immunology Workgroup, Frankfurt, 03.-04.11.2006]. / Bericht über die 34. Tagung des Arbeitskreises Klinische Immunologie, Frankfurt, 03.-04.11.2006.

The annual meeting of the Clinical Immunology Workgroup focused on autoimmune vasculitides. The role of innate immunity, T- and B-cells, and innovative therapies for autoimmune vasculitides was discussed. Further topics of the meeting were the role of endothelial microparticles, ghrelin and leptin, regulatory and effector-memory T-cells in ANCA-associated vasculitides, as well as the lethal midline granuloma, intracytoplasmic cytokine-profile in Behcet's disease, autoantibodies in rheumatoid arthritis, polyarteritis nodosa with cranial manifestation, ILT6 as genetic marker in multiple sclerosis and Sjögren's syndrome, alpha-fodrin autoantibodies in multiple sclerosis, interferon-g autoantibodies in a patient with atypical mycobacteriosis, and autoreactive T-cells in murine lupus.

[Diagnosis und therapy of ANCA-associated vasculitis]. / Diagnostik und Therapie der ANCA-assoziierten Vaskulitiden.

The diagnosis of ANCA-associated vasculitides (AAV) consists of clinical symptoms, results of technical procedures and a characteristic histology. The diagnostic workup should focus on the prominent clinical symptoms and should involve an interdisciplinary team of specialists. The therapy is divided into induction and maintenance treatment. Cyclophosphamid remains standard therapy for the induction of remission, whereas azathioprine, methotrexate and leflunomide are often used for maintenance therapy. The introduction of a stage-adapted treatment has contributed to a significant improvement of the long-time prognosis of patients with AAV.

Balloon angioplasty of arteries of the upper extremities in patients with extracranial giant-cell arteritis.

OBJECTIVES: To evaluate the outcome of balloon angioplasty in the arteries of the upper extremities in patients with giant-cell arteritis (GCA) and stenosing extracranial involvement. METHODS: Percutaneous transluminal angioplasty (PTA) for symptomatic upper limb artery stenoses (n = 29) and occlusions (n = 1) resistant to medical treatment was carried out in 10 patients (all women, mean age 65 years) with GCA. Vascular lesions were located in the subclavian (n = 4), axillary (n = 10) and brachial (n = 16) arteries. Interventional treatment was accompanied by immunosuppressive drugs in all patients. Follow-up included clinical and serological examination, magnetic resonance angiography and colour duplex ultrasound. RESULTS: Initial technical success of angioplasty was achieved in the case of all vascular lesions. In five patients, marked recurrent stenoses (vascular territories; n = 10/30) were found during follow-up (mean 24 months). The cumulative primary patency rate was 65.2%. All recurrent lesions developed in the territories of the initial long-segment stenoses. Repeated PTA (vascular territories, n = 8; patients, n = 5) provided a cumulative secondary patency rate of 82.6% and a cumulative tertiary patency rate of 89.7%. CONCLUSIONS: Despite a tendency to restenoses, balloon angioplasty of the upper-extremity artery, in combination with immunosuppressive treatment, is an efficient method for the treatment of extracranial GCA.

Lack of efficacy of rituximab in Wegener's granulomatosis with refractory granulomatous manifestations.

OBJECTIVE: To investigate the safety and efficacy of rituximab (RTX) in patients with refractory Wegener's granulomatosis (WG). PATIENTS AND METHODS: Eight consecutive patients with active refractory WG were included. In all patients disease activity had persisted despite standard treatment with cyclophosphamide and prednisolone, as well as tumour necrosis factor alpha blockade 3 months before inclusion in the study. Patients had particular granulomatous manifestations like retro-orbital granulomata (n=5), nodules of the lungs (n=1), and subglottic stenosis (n=2). RTX was given intravenously every 4th week in combination with the standard treatment in five patients and with methotrexate in two others. Disease extent and activity were monitored clinically by interdisciplinary care, immunodiagnostics (ANCA serology, B cells by flow cytometry), and magnetic resonance imaging. RESULTS: Beneficial response and a reduction in disease activity were seen in three patients, two of whom went into complete remission. In three other patients, disease activity remained unchanged while the disease progressed in the remaining two patients. In all patients peripheral blood B cells fell to zero during treatment with RTX. cANCA titres remained unchanged in all except one patient. CONCLUSION: In this pilot study, B lymphocyte depletion was not associated with a change of the ANCA titres or obvious clinical improvement of refractory granulomatous disease in patients with WG. Further studies are needed to evaluate the role of RTX in WG.

[Early diagnosis of vasculitides]. / Frühdiagnose von Vaskulitiden.

The often unspecific symptoms like myalgias, fever and weight loss at the onset of vasculitides are a frequent cause for a delay in diagnosis. Organ-specific symptoms like hemoptysis, dyspnoea, epistaxis, edema and organ infarcts a present when organ dysfunction occurs as a result of vasculitis. Targeted serologic testing including antineutrophil cytoplasm antibodies (ANCA) and cryoglobulins allows early diagnosis of certain vasculitides. Modern imaging techniques like magnetic resonance imaging, computed tomography, positron-emission tomography and ultrasound are cornerstones for an early diagnosis as they allow the detection of subclinical disease and are helpful in the identification of a site for biopsy. Bioptic proof of vasculitis is still the gold standard for diagnosis. Functionally relevant damage caused by systemic inflammatory disorders can by reduced or sometimes avoided by early initiation of treatment. This requires a correct diagnosis is made as early as possible.

[Symmetric polyarthritis in a patient with Churg-Strauss syndrome]. / Symmetrische Polyarthritis bei einem Patienten mit Churg-Strauss-Syndrom.

HISTORY: A 63-year-old man developed a Churg-Strauss syndrome with predominantly motor-sensory polyneuropathy. Initial treatment with cyclophosphamide and steroids achieved complete remission. Subsequent relapse with marked retinal vasculitis at first was refractory to the standard treatment. Renewed remission was obtained with additional infliximab, and was maintained with azathioprine for 12 months before the patient again presented with symmetrical polyarthritis. INVESTIGATIONS: Clinical examination revealed a symmetrical polyarthritis involving the joints of the hand and fingers. The acute-phase parameters were raised, the rheumafactor was highly positive. Radiology showed early erosions in the bones of the hand. There were no indices of renewed activity of the Churg-Strauss syndrome. TREATMENT AND COURSE: These findings indicated sero-positive rheumatoid arthritis and methotrexate was started, later supplemented with sulfsalazine and hydroxychloroquine because of continuing signs of activity. Infliximab was again given because of further progression, but a severe infusion reaction developed during the second infusion. After changing to etanercept remission of the rheumatoid arthritis was achieved. CONCLUSION: The development of rheumatoid arthritis during remission achieved with azathioprine in Churg-Strauss syndrome of four-year duration is very rare. Repeated dosis of infliximab at long intervals greatly increases the risk of an intolerance.

[Glucocorticoids: importance in the treatment of vasculitis]. / Glucocorticoide: Stellenwert in der Therapie der Vaskulitis.

Only the modification of natural steroids in the middle of the last century gave insights into the structural requirements for the biological activity of the glucocorticoids (GC). While the delta-4,3-keto-11-beta, 17-alpha,21-trihydroxyl configuration is needed for the GC-activity, an artificial additional double binding in position 1 and 2 lead to a four fold increase of the GC-activity. Of the artificial GC, prednisolone is the most frequently used compound and essential in the therapy of vasculitis today. Dosage, duration and way of application depend on the diagnosis, disease stage, -extend as well as -activity. Considering the use and side-effects of the GC, experiences from cohort-studies of the late 80-ties help at clinical decision making. For giant cell arteritis (GCA) it was shown, that doses of less then 60 mg/day are needed for the induction of remission. Concerning the visual loss in GCA, time of initiating GC-therapy seems more important than the dosage. In the treatment of ANCA-associated vasculitis therapy with GC, later in combination with cyclophosphamide, lead to a significant reduction of mortality. Due to the fact of an increasing survival rate, therapy-related morbidity becomes a more and more important issue. There is a proven correlation between the dosage respectively duration of the GC-therapy and the risk of GC-associated side-effects, especially the incidence of severe infections. This article gives a short review of the present data of the role of GC in the treatment of vasculitis.

[Subcutaneous magnesium pump in a patient with combined magnesium transport defect]. / Subkutane Magnesiumpumpe bei einem Patienten mit kombiniertem Magnesiumtransportdefekt.

HISTORY AND ADMISSION FINDINGS: A 28-year-old man, known to have abnormal intestinal magnesium absorption, presented with recurrent cerebral seizures. Despite daily intravenous sulphate infusions, magnesium concentration remained inadequate. Physical examination was unremarkable. INVESTIGATIONS: Serum magnesium concentration was markedly reduced to 0.48 mmol/l. The parenteral magnesium tolerance test indicated reduced enteric magnesium absorption of < 20%. Absolute magnesium concentration in 24-hour urine was normal at 6.3 mmol/24 h, but high in proportion to the hypomagnesaemia. All other laboratory data were within normal limits. TREATMENT AND COURSE: In addition to the known intestinal malabsorption the patient also had isolated renal loss of magnesium. It was only by continuous magnesium infusion with a recently developed portable subcutaneous pump system that normal serum magnesium concentrations were attained and all symptoms disappeared. CONCLUSION: This patient has combined magnesium transport defects, which could not be effectively treated by conventional methods, but required continuous magnesium infusion with an indwelling subcutaneous infusion pump. This case serves as an example of the way in which subcutaneous infusion can provide physiological substitution of electrolytes.