Cees G. M. Kallenberg

Prevention of relapsing disease in anti-neutrophil cytoplasmic antibody related necrotizing small-vessel vasculitis: the role for autoantibody guided and anti-bacterial treatment

Within the spectrum of primary vasculitic syndromes, the anti-neutrophil cytoplasmic antibody (ANCA) related syndromes form a distinct group with overlapping features. ANCA related small-vessel vasculitides are potentially life-threatening diseases with high mortality. Prolonged immunosuppressive therapy (> 1 year) with cyclophosphamide and steroids is effective in inducing disease remission and preventing early relapses in most vasculitic disorders [1-6]. Continuous use of cyclophosphamide to sustain remission cannot be recommended, however, since this treatment regimen is associated with severe and potentially lethal adverse effects such as the occurrence of opportunistic infections and the development of malignancies [7, 8]. Therefore, cyclophosphamide is tapered or stopped once remission is achieved to prevent adverse effects. Alternatively, azathioprine may be used as maintenance therapy after a remission is induced with cyclophosphamide and steroids [5]. Azathioprine is considered less effective in inducing remission than cyclophosphamide, but its long-term toxicity is much lower [9, 10]. The potential of azathioprine as maintenance therapy was recently investigated and compared with cyclophosphamide in a large randomized trial (CYCAZAREM) [11-13]. Following induction therapy with oral cyclophosphamide and steroids, maintenance treatment with azathioprine was as effective as the continued use of cyclophosphamide in the prevention of disease relapse during a 15-month follow-up period in this study. Other alternative maintenance therapy regimens, such as methotrexate [14], cyclosporin A [15], or mycophenolate [16] have been described but have not been tested adequately until now.

Standard therapeutic regimens for vasculitis

Necrotizing systemic vasculitis was described nearly 135 years ago as a fatal condition [1]. Early reports of these forms of vasculitis indeed documented a rapidly progressive course with death occurring within months of diagnosis [2, 3]. Treatment with corticosteroids reduced the 1-year mortality, but after 3 years no difference in mortality was found between treated and untreated patients [4]. Since the introduction of a combination of cyclophosphamide and steroids, however, the outcome of vasculitis has dramatically changed, and 1-year survival has increased to 70-99% [5-9]. Vasculitis has now become a chronic disorder with accumulating morbidity resulting in impairment of employability, functional status, and social activities [10, 11]. The costs for vasculitis-related hospitalizations in the USA were roughly calculated to be over

Pulmonary Manifestations of Systemic Vasculitides

150 million per year [12]. There is a constant need to improve therapeutic protocols for vasculitis since current protocols are toxic, contribute to morbidity and mortality, and are not always effective. Novel approaches that recently became available include therapy with mycophenolate and/or 15-deoxyspergualin (see the chapter by Stegeman and Birck in this volume), intravenous immunoglobulin (see the chapter by Jayne), tumor necrosis factor α (TNFα) directed therapy (see the chapter by Stone), anti-thymocyte globulin and anti-CD52/anti-CD4 therapy (see the chapter by Schmitt et al.), and immunoablation with or without stem cell rescue (see the chapter by Carruthers and Bacon). These novel approaches offer the possibility to treat patients with a less toxic and/or more effective treatment modality than with the therapeutic regimens that are currently used as “standard regimens”. These latter will be reviewed in this chapter.

Disease-modifying therapy in vasculitides

The term “vasculitis” denotes a pathological process characterized by inflammation and necrosis of blood vessel walls. The vasculitic process can affect blood vessels of any type, size or location, and therefore can cause dysfunction in virtually any organ system, including the lungs. Pulmonary manifestations such as nodular shadows and/or infiltrative changes on the chest radiograph are often present in an early phase of the disease process, and in patients with arthralgias and/or constitutional symptoms, the presence of these pulmonary abnormalities should alert the clinician to the possibility of vasculitis. Vasculitis frequently affects the lung, and sometimes the lung is the only organ involved. Recent studies have shown that cytokines and adhesion molecules that mediate normal leukocyte function are involved in the pathogenesis of vasculitis [1, 2]. Pathological expression of adhesion molecules and production of cytokines may result from different initiating events. Indeed, several types of pathophysiological events that may lead to vessel wall damage are recognized currently. These include pathogenic immune complex deposition or in situ formation, a “Shwartzman-like” phenomenon in which intravascular activation and aggregation of neutrophils may be operative, antibody-dependent cell-mediated cytotoxicity, and cell-mediated immune responses [1, 3]. For therapeutic purposes, it would be useful to categorize different forms of vasculitis based on specific mechanisms of vessel damage. Classification of vasculitides is unfortunately, however, only partly based on our understanding of pathogenetic mechanisms. Although classification of vasculitides is still not perfect, enormous progress has been made in recent years. Firstly, a universally accepted classification scheme has emerged [4], and classification criteria for major vasculitic syndromes have been published [5], whereas at a consensus conference definitions for the most common forms of vasculitis have been adopted [4].

Systemic vasculitides, an introduction

Systemic vasculitides, an introduction.- Standard therapeutic regimens for vasculitis.- Tumor necrosis factor (TNF) inhibition in the treatment of vasculitis.- Methotrexate as an alternative to classic immunosuppressive therapies.- Intravenous immunoglobulin as immuno-modifying treatment.- T-cell directed treatment: anti-thymocyte globulin.- New immunosuppressants: mycophenolate mofetil and 15-deoxyspergualin.- Interferon-? for the treatment of virus-related systemic vasculitides.- Autologous stem cell therapy for systemic vasculitis.- Prevention of relapsing disease in anti-neutrophil cytoplasmic antibody related necrotizing small-vessel vasculitis: the role for autoantibody guided and anti-bacterial treatment.

Anti-Neutrophil Cytoplasmic Antibodies (ANCA): New Tools in the Diagnosis and Follow-Up of Necrotizing Glomerulonephritis and Vasculitis

Vasculitis is a condition characterized by inflammation of blood vessels. Its clinical manifestations are dependent on the localization and size of the involved vessels as well as on the nature of the inflammatory process. Vasculitis can be secondary to other conditions or constitute a primary, in most cases, idiopathic disorder. Underlying conditions in the secondary vasculitides are infectious diseases, connective tissue diseases, and hypersensitivity disorders. Immune complexes, either deposited from the circulation or formed in situ, are involved, in many cases, in the pathophysiology of the secondary vasculitides. Those complexes are supposedly composed of microbial antigens in case of underlying infectious diseases, autoantigens in the connective tissue diseases, and non-microbial exogenous antigens in the hypersensitivity disorders (Tab. 1). Although immune deposits can be demonstrated in the involved vessel wall by direct immunofluorescence of biopsy material, the specificities of the antigens and their corresponding antibodies have not been demonstrated in most of the cases.

Neutrophil activation in vitro and in vivo in Wegener's granulomatosis

Vasculitis refers to an inflammatory process affecting blood vessels. It may represent a manifestation of disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis or mixed cryoglobulinemia, or constitutes the major and primary hallmark of a number of clinical syndromes (1–7). Within the spectrum of vasculitis the latter group of the so-called idiopathic systemic vasculitides is a pathogenetically poorly understood group of diseases that can be classified according to the size of the vessels involved (6,7) (Table 1).