P. M. Aries

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 α 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.

INTRAVENOUS IMMUNOGLOBULIN THERAPY IN VASCULITIS: SPECULATION OR EVIDENCE?

Initially, intravenous immunoglobulins (IVIgs) were used as replacement therapy in primary and secondary antibody-deficiency syndromes. The clinical use of IVIg has been extended during the past decade to a wide variety of clinical conditions, such as infectious processes, neuroimmunological diseases, and different systemic autoimmune diseases. The mode of action of IVIg is complex, involving modulation of the Fc receptors, interference with the complement and cytokine network, and effects on the activation and differentiation of T-and B-cells.Kawasaki disease (KD) was one of the first diseases within the group of primary vasculitides in which IVIg were used. Today, there is a clear evidence of benefit for IVIg in the treatment of coronary artery abnormalities related to KD. Subsequently, various reports have suggested a beneficial effect in other vasculitides; however, there are few data from controlled studies. For antineutrophil cytoplasmic antibody-associated vasculitis (AAV) one placebo-controlled and several open-label studies have shown a beneficial effect on the disease activity in patients with Wegener’s granulomatosis or microscopic polyangiitis refractory to standard therapy with prednisone and cyclophosphamide. For other vasculitides, such as polyarteritis nodosa or Henoch-Schonlein purpura, only case reports have described an inhibition of a disease progression by IVIg so far. However, the effect was partly only temporary. In conclusion, KD and AAV are the only vasculitides with a definite beneficial use of IVIg. For other vasculitides, the efficacy of IVIg has not been proven properly but may be useful in single cases.

Successful use of bortezomib in a patient with systemic lupus erythematosus and multiple myeloma

Bortezomib belongs to the family of proteasome inhibitors and is a well established first line drug in multiple myeloma (MM).1 In mouse models of lupus nephritis, bortezomib ameliorated glomerulonephritis, prolonged survival and reduced autoantibody production.2 We report the case of a 63-year-old woman who presented with systemic lupus erythematosus (SLE) fulfilling the American College of Rheumatology (ACR) criteria and requiring treatment for autoimmune thrombocytopoenia, Coombs positive autoimmune haemolytic anaemia, polyarthritis and hair loss. Anti-nuclear antibody (ANA), extractable nuclear antigen (ENA) (U1 riboucleoprotein (U1RNP)) and anti-double-stranded (ds)DNA antibody tests were positive, and serum complement C3 and C4 levels were decreased (European Consensus …

Current State of Biologicals in the Management of Systemic Vasculitis

Abstract:  Conventional immunosuppressive treatment of systemic vasculitides has improved their often fatal outcome, but is burdened by cytotoxic side effects and frequent relapses. Recent advances in the therapy of systemic vasculitides with biologicals have helped to establish new options for patients resistant to conventional treatment. Moreover, early intervention aiming to interfere with specific targets important in the break of tolerance and/or persistence of the autoimmune response might further improve the prognosis of autoimmune vasculitides such as antineutrophil cytoplasmic autoantibody (ANCA)‐associated vasculitides (AAV). In vitro and in vivo studies suggest that the interaction of ANCA and cytokine (TNF‐α, IL‐1)‐primed neutrophils results in premature neutrophil activation and degranulation, subsequent endothelial cell damage, and further leukocyte recruitment. For one of the AAV, Wegeners granulomatosis, recent ex vivo data have provided evidence that WG‐granulomata might provide the necessary “proinflammatory environment” for the break of tolerance and display features of lymphoid‐like tissue neoformation, in which autoimmunity to “Wegeners autoantigen” proteinase 3 PR3 could be sustained. Blocking TNF‐α and eliminating autoreactive B cells seem promising treatment targets to interfere with these fundamental disease processes. While the recombinant TNF‐α receptor/IgG1 fusion protein etanercept, in addition to standard therapy with subsequent tapering of standard medications, was found to be not effective for maintenance of remission, open clinical studies suggest a beneficial effect of the anti‐TNF‐α antibody infliximab in addition to standard therapy for the induction of remission in patients with refractory AAV. Peripheral B cell depletion with the anti‐CD20 antibody rituximab also induced remissions in AAV in uncontrolled trials.

The low-penetrance R92Q mutation of the tumour necrosis factor superfamily 1A gene is neither a major risk factor for Wegener’s granulomatosis nor multiple sclerosis

Inherited autosomal-dominant mutations in the tumour necrosis factor receptor superfamily 1A ( TNFRSF1A ) gene encoding the tumour necrosis factor receptor p55 (TNF-R1) are the cause of an auto-inflammatory syndrome that is characterized by periodic fever attacks, aseptic peritonitis, arthritis, meningitis, conjunctivitis, pleuritis and skin rash (OMIM #142680). The most common TNFR-associated periodic syndrome (TRAPS)-like disease that is associated with a R92Q mutation, however, occurs sporadically, with later onset (median 23 years vs 7 years with other mutations) and a milder and often oligosymptomatic course.1,2 Intriguingly, carriers of the R92Q allele bear a slightly increased risk for some other diseases, such as myocardial infarction,3 increased carotid intima-media thickness,3 thrombotic complications in Behcet’s disease4 and early synovitis.1 Due to the low …

Biological therapies: new treatment options for ANCA-associated vasculitis?

Biological therapies enable us to apply highly selective targeting components to modulate the immune response. Until now, a few controlled studies investigated the efficacy of TNF-α blocking agents in systemic vasculitis have been carried out, but, in general, they were falling short of expectations. However, there is conducive evidence that TNF-α blockers are advantageous in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis, at least in selected disease stages. Likewise, although the efficacy of the monoclonal CD20 antibody rituximab in ANCA-associated vasculitis is obvious, the effect on predominantly granulomatous disease activity in Wegener’s granulomatosis is less clear. In addition, interferon-α is used for induction treatment particularly in Churg-Strauss syndrome. Even though the effectiveness and safety of short-term administration was confirmed by case series, severe side effects after long-term treatment relativized the initial results. This review presents the recent data on the use of biologicals in vasculitis and appraises the knowledge in the clinical context.

A case of destructive Wegener's granulomatosis complicated by cytomegalovirus infection

Background A 63-year-old man with a 4-year history of Wegeners granulomatosis presented with hemoptysis, palatal ulceration and sensorimotor polyneuropathy.Investigations Physical examination, serologic testing, proteinase 3 enzyme-linked immunosorbent assay, IgG and IgM specific to Epstein–Barr virus enzyme-linked immunosorbent assay, MRI of the middle face, an ear, nose and throat consultation, immunohistochemical staining of an esophageal sample obtained from esophagogastroduodenoscopy, polymerase chain reaction of cytomegalovirus (CMV) DNA from esophageal and blood samples, and measurement of pp65 early antigen.Diagnosis Wegeners granulomatosis with progressive palatal ulceration and osseous destruction complicated by CMV-related esophagitis during induction treatment.Management Induction treatment with cyclophosphamide pulse therapy was discontinued and antiviral therapy with ganciclovir was started. Cyclophosphamide pulse therapy was later reintroduced, but there was subsequent CMV reactivation, and, therefore, cyclophosphamide pulse therapy was suspended again and ganciclovir and intravenous immunoglobulin were started. After control of CMV, cyclophosphamide pulse therapy was reinitiated. Prolonged immunosuppressive therapy controlled disease activity, without CMV reactivation.

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.ZusammenfassungDie häufig noch uncharakteristischen Symptome bei Erstmanifestation einer Vaskulitis wie Myalgien, Fieber und Gewichtsverlust führen nicht selten zu Verzögerungen in der Diagnosestellung. Organspezifischere Symptome wie Hämoptysen, Dyspnoe, Epistaxis, Ödeme oder Organinfarkte treten hinzu, wenn als Folge der Vaskulitis bereits eine Funktionsminderung der betroffenen Organsysteme besteht. Eine gezielte serologische Diagnostik, insbesondere die Bestimmung von anti-neutrophilen zytoplasmatischen Antikörpern (ANCA) oder Kryoglobulinen kann eine frühe Diagnosestellung von Kleingefäßvaskulitiden erleichtern. Moderne bildgebende Verfahren wie die Magentresonanztomographie, Computertomographie, Positronenemissionstomographie und Sonographie sind für die Frühdiagnose von Vaskulitiden bedeutsam, da sie eine Diagnose oft noch subklinischer Manifestationen ermöglichen und die Auswahl eines Ortes zur Gewinnung einer Biopsie erleichtern. Die bioptische Sicherung ist immer noch der Goldstandard in der Diagnostik der Vaskulitiden.Funktionell relevante Spätschäden als Folge einer Vaskulitis können durch eine frühzeitig eingeleitete Therapie in ihrer Schwere deutlich reduziert werden. Voraussetzung hierfür ist die möglichst frühe und präzise Diagnosestellung.SummaryThe often unspecific symptoms like myalgias, fever and weight loss at the onset of vasculitides are a frequent cause for a delay in diagnosis. Organspecific 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.

Early diagnosis of vasculitides

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.ZusammenfassungDie häufig noch uncharakteristischen Symptome bei Erstmanifestation einer Vaskulitis wie Myalgien, Fieber und Gewichtsverlust führen nicht selten zu Verzögerungen in der Diagnosestellung. Organspezifischere Symptome wie Hämoptysen, Dyspnoe, Epistaxis, Ödeme oder Organinfarkte treten hinzu, wenn als Folge der Vaskulitis bereits eine Funktionsminderung der betroffenen Organsysteme besteht. Eine gezielte serologische Diagnostik, insbesondere die Bestimmung von anti-neutrophilen zytoplasmatischen Antikörpern (ANCA) oder Kryoglobulinen kann eine frühe Diagnosestellung von Kleingefäßvaskulitiden erleichtern. Moderne bildgebende Verfahren wie die Magentresonanztomographie, Computertomographie, Positronenemissionstomographie und Sonographie sind für die Frühdiagnose von Vaskulitiden bedeutsam, da sie eine Diagnose oft noch subklinischer Manifestationen ermöglichen und die Auswahl eines Ortes zur Gewinnung einer Biopsie erleichtern. Die bioptische Sicherung ist immer noch der Goldstandard in der Diagnostik der Vaskulitiden.Funktionell relevante Spätschäden als Folge einer Vaskulitis können durch eine frühzeitig eingeleitete Therapie in ihrer Schwere deutlich reduziert werden. Voraussetzung hierfür ist die möglichst frühe und präzise Diagnosestellung.SummaryThe often unspecific symptoms like myalgias, fever and weight loss at the onset of vasculitides are a frequent cause for a delay in diagnosis. Organspecific 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.

Periostitis as the initial manifestation of systemic vasculitis

The greatest challenge in diagnosing vasculitis is the diversity of its clinical presentation. Awareness of the heterogeneity of uncommon manifestations can be decisive for the course of the disease. We report on a patient presenting with periostitis as the initial manifestation of systemic vasculitis. A 38 year old female patient complained about progressively painful swelling and reddening of the distal right lower leg for several weeks. The patient had been healthy until then and had no history of arterial or venous insufficiency. She presented at hospital with reduced pulses and a severe compartment syndrome of the tibialis anterior compartment. An x ray examination showed typical signs of periostitis …