Jan Willem Cohen Tervaert

CONTEMPORARY CHALLENGES IN AUTOIMMUNITY

Introduction: It is hypothesized that IgM antibodies to oxidized LDL are anti‐atherogenic. Myeloperoxidase from plaque‐infiltrating neutrophils catalyzes the production of hypochlorite (HOCl), which oxidizes LDL. Here we study the IgM response to HOCl‐modified LDL in comparison to titers of T15 clonotypic natural antibodies. Methods: Plasma of LDLR−/− mice fed a normal chow or high‐fat diet was obtained after 6 and 16 weeks. The IgM responses to HOCl‐modified LDL and T15 clonotypic natural IgM antibodies were measured by ELISA. Results: The IgM levels in response to HOCl‐modified LDL increased dramatically in the atherosclerotic group after introduction of the high‐fat diet, but not in mice on normal chow. The natural IgM T15 clonotypic antibody titers revealed a more moderate increase during atherogenesis. Conclusion: Our results show that during atherogenesis there is a strong induction of IgM antibodies to HOCl‐modified LDL particles. Whether these induced IgM antibodies are pro‐ or anti‐atherogenic remains to be established.

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.

ANCA Diagnostics in Clinical Practice: New Developments

Anti-neutrophil cytoplasmic antibodies (ANCA) are the hallmark of the so-called ANCAassociated vasculitides (AAV) (Jennette & Falk, 1997). These primary small-vessel vasculitides comprise granulomatosis with polyangiitis (GPA, previously referred to as Wegener’s granulomatosis) (Falk et al, 2011), the Churg-Straus syndrome (CSS), microscopic polyangiitis (MPA), and renal-limited necrotizing crescentic glomerulonephritis (NCGN). These disease entities can be discriminated based on systemic symptoms of disease (GPA, CSS, and MPA) versus clinical manifestations that are restricted to the kidneys (NCGN). The systemic diseases can further be subdivided by the presence (GPA and CSS) or absence (MPA) of granulomatous lesions in the airways, while GPA and CSS can be distinguished based on the presence of asthmatic manifestations and/or eosinophilia in CSS, but not in GPA. Classification criteria for these diseases have been defined by the American college of rheumatology (ACR; Fries et al, 1990) and the Chapel Hill consensus conference (Jennette, 1994). The presence of ANCA, however, is not part of these criteria which are primarily based on clinical manifestations and histopathology as observed in biopsies obtained from the affected tissues. More recently a novel consensus methodology for the classification of AAV was developed and validated for epidemiological studies (Watts et al, 2007). Importantly, the latter classification criteria incorporated the ANCA status of the patient. By definition ANCA are directed to the cytoplasmic components of neutrophilic granulocytes. In particular the constituents of the granules appear to be the antigenic targets. With respect to AAV the serine protease (PR)3 and myeloperoxidase (MPO) are the most important autoantigens. ANCA were originally detected by indirect immunofluorescence (IIF) on ethanol-fixed neutrophils. According to the international consensus on ANCA detection four patterns have to be distinguished (Savige et al, 1999). First, the classical (C-)ANCA is characterized by a granular, cytoplasmic fluorescence with central or interlobular accentuation; second, a diffuse flat cytoplasmic fluorescence without interlobular accentuation may be referred to as atypical C-ANCA. In clinical practice, however, this pattern is not distinguished by many clinical laboratories. Third, the perinuclear (P-)ANCA is characterized by perinuclear staining, with or without nuclear extension. Reading of the P-ANCA pattern may be hampered by the presence of interfering antinuclear antibodies (ANA). Finally, if a combination of cytoplasmic and perinuclear staining occurs, this is called atypical ANCA. The perinuclear staining pattern actually is an artefact, since formalin-fixation produces a cytoplasmic staining pattern, indistinguishable

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].

43 - Infections and Vasculitis

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.

Systemic vasculitides, an introduction

Atherosclerosis and vasculitis are inflammatory vascular disorders. A number of infectious agents and conditions have been associated with atherosclerosis and many potential mechanisms have been hypothesized to result in atherothrombogenesis. Infectious agents that are especially associated with atherosclerosis are cytomegalovirus (CMV), Chlamydia pneumoniae, and helicobacter pylori. Gingivitis has been associated with atherosclerosis. The evidence that infectious agents may be involved in atherogenesis does not yet prove a causal relationship. For vasculitis, the evidence for an infectious agent in the pathophysiology is much stronger. However, here, the evidence is restricted to few patients, and in most of the patients with vasculitis no clear infectious agent can be convincingly demonstrated. This chapter presents the evidence for a role of infectious agents in vasculitis. Infectious agents have been clearly demonstrated in various vasculitides. Direct evidence of a pathophysiological role of specific microbial agents is, however, scarce. Recently developed molecular approaches such as DNA microarrays may be helpful in studying this issue in the near future.

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).