Current Immunology Reviews (Discontinued) - Volume 7, Issue 4, 2011

Wegener's granulomatosis (WG) was described in 1936 [1], Churg-Strauss syndrome (CSS) in 1951 [2], and microscopic polyangiitis (MPA) was formally recognized in 1994 [3]. These three conditions have been linked under the umbrella term of ANCA associated vasculitis (AAV) due to their association with antibodies directed against antigens in the neutrophil cytoplasm (ANCA). All three conditions produce necrotising vasculitis of medium and small vessels with differing predilections to various organs. Although these conditions have been recognized since the 1930's, the first clinical trial was not published till 1983. Fauci et al. shared their experience of using open label, uncontrolled oral cyclophosphamide and glucocorticoid combination therapy in patients with WG [4]. That paper described 85 patients recruited in one centre over 21 years. 27 years later, two randomised clinical trials were published in the same week [5-6]. Between the two, the papers described 245 patients with WG or MPA recruited over 4 years and followed up for predefined durations in 17 centres across the world. Compared to the first 60 years of WG, our understanding and thus our methodology of investigating potential therapies for these conditions has changed dramatically. In the last decade there have been 12 randomised controlled trials in patients with AAV (Table 1). It has taken a huge amount of co-ordinated effort to overcome the challenges of studying these relatively rare conditions. Till the Chapel Hill Consensus conference (CHCC), MPA had not been formally defined, although its existence distinct from polyarteritis nodosa (PAN) had been recognised [3]. Prior to the CHCC definitions it was common to club together MPA and even CSS under the umbrella of ‘PAN’. Although these definitions are not diagnostic, they have been of value in identifying homogenous populations for clinical trials. This in turn led to the recognition that the different AAV may have different clinical outcomes [7]. The first clinical trials in AAV were single centre studies. This often meant that the studies were either underpowered, took a long time to recruit adequate numbers of patients, or mixed the differing vasculitis syndromes. All of these problems often made the data difficult to interpret. This problem brought together vasculitis researchers to form research groups. The French Vasculitis Group (FVSG), the European Vasculitis Study Group (EUVAS) and the American Vasculitis Clinical Research Consortium (VCRC) were born out of efforts to conduct meaningful vasculitis research. Of the 12 RCT’s conducted in the last decade (Table 1), 10 have been from these three groups. After the discovery of ANCA, there was hope that this could perhaps serve as a biomarker for activity in patients with AAV. Initial studies suggested that treating patients according to ANCA levels prevented relapse [8], but the present general consensus does not support treatment changes based on serial ANCA monitoring alone [9]. In the absence of valid biomarkers, the invention of structured clinical examination and monitoring has become the accepted surrogate for disease activity. Various clinical tools have been used to measure disease activity, but the one that has been accepted as consensus has been the Birmingham Vasculitis Activity Score (BVAS) [10]. Of the 12 RCT's in the past decade, 9 have used different versions of the BVAS as the outcome measure, and the other 3 applied the BVAS retrospectively as they had started recruiting patients prior to the validation of the first version of BVAS. The use of a single validated clinical tool to measure disease activity in all the clinical trials has made it possible to compare outcomes from different clinical trials. Clinical trials in AAV can be divided into those for inducing remission and those for preventing a relapse. However, the definitions of remission and relapse have been widely different across the clinical trials. This has been discussed in detail elsewhere [11], but in brief, the definition of remission has varied from “When the patient's general condition improved, no new manifestations of WG appeared, and the ESR returned to normal” [12] to being as strict as “Absence of clinical, serologic”, and radiologic (including MRI) evidence of disease activity. These conditions had to be sustained for at least 6 months after the discontinuation of pulse CYC treatment, without further immunosuppressive therapy, including withdrawal of prednisolone” [13]. Of the 12 clinical RCT's in Table 1, 8 were designed to trial therapies for remission induction. Of the 8, 5 had remission (as defined by BVAS = 0) as the primary outcome. Similarly relapse has also been defined by the reappearance of clinical manifestations which could be scored on the BVAS. From the examples of the definitions of remission, it can be seen that a specified disease state can mean different things in different clinical trials. The European League Against Rheumatism (EULAR) has attempted to standardize these definitions and indeed the entire conduct of clinical trials in AAV [14]. However, the exact nature of definitions still varies and cannot be compared across clinical trials without looking at the raw data again. For example, remission was defined as BVAS (v.3) = 0 for 6 months in Jones et al. [6], and BVAS/WG = 0 off prednisolone in Stone et al. [5].....

The aetiology of the systemic vasculitides is unknown, clues to the causation may be revealed by their epidemiology. The epidemiology of vasculitis poses considerable challenges to epidemiologists. These challenges include the difficulty of defining a case with a lack of clear distinction between the different disorders, case capture and case ascertainment. The vasculitides are generally rare and therefore a large population is required to accurately determine incidence and prevalence, and this poses questions of feasibility. Nonetheless, despite these difficulties a considerable body of data on the epidemiology of the vasculitides has developed over the past 30 years with interesting age, geographic and ethnic tropisms gradually being revealed. Most of the data comes from Caucasian populations of European descent. In this article we describe the epidemiology of systemic vasculitis focusing on possible risk factors such as age, ethnicity, infection, drugs and other possible environmental agents.

There are currently no diagnostic criteria for the systemic vasculitides. Due to the heterogeneous and non specific manner that vasculitis can present there is often a delay in diagnosis which translates to increase morbidity and mortality. The current disease definitions and classification criteria are often misapplied as diagnostic criteria, but evaluation of this has shown that they do not perform satisfactorily for this purpose. We discuss the CHCC definitions, the ACR classification criteria and the EMEA algorithm which is needed to bridge the inconsistency between the two. We also evaluate the FVSG proposal for polyarteritis nodosa, and attempts of the Behcet's disease community to develop diagnostic criteria. We provide a brief summary of how a diagnosis of vasculitis is currently made, describe how increased understanding of disease mechanisms has identified biomarkers which aid diagnosis, and describe how clinically applicable diagnostic criteria could be developed.

Positron emission tomography is a valuable aid in the diagnosis of atypical cases of giant cell arteritis, Takayasu arteritis and polymyalgia rheumatica. It has broadened our knowledge on the vascular involvement in these disorders and has thrown new light on the relationship of giant cell arteritis and polymyalgia rheumatica.

Both PR3-ANCA and MPO-ANCA are highly sensitive and specific markers for the ANCA-associated vasculitides (AAV), in particular granulomatosis with polyangiitis and microscopic polyangiitis. This close association suggests a pathogenic role of the autoantibodies. In vitro and in vivo experimental data strongly support such a role, particularly for MPO-ANCA. As pathogenic autoantibodies ANCA could serve as biomarkers for AAV. Longitudinal observations indeed prove that MPO-ANCA could serve as a biomarker for AAV although being not perfect. For PR3- ANCA, data are less convincing as some studies found a fair correlation between changes in levels of PR3-ANCA and disease activity of the AAV, but others found not. This could be due to methodological shortcomings but also to inherent differences in pathogenicity between MPO-ANCA and PR3-ANCA. More studies are needed to solve this question.

The important role of B cells in the pathogenesis of systemic vasculitis has become increasingly clear over recent years. B cell directed therapies offer an exciting new approach to the treatment of these conditions, in which there has been little change in the options available to managing clinicians since the advent of traditional immunosuppressive therapy. The introduction of conventional immunosuppression has transformed survival in systemic vasculitis, particularly ANCA-associated vasculitis, but at the expense of significant toxicity, and with suboptimal efficacy. B cell therapies offer the possibility of targeted, individually tailored immunotherapy, which by improving efficacy, and reducing toxicity will improve clinical outcomes in systemic vasculitis. However, the heterogeneity of vasculitic syndromes suggests that one agent is unlikely to be effective in all situations. The precise indications and optimal combination of B cell directed with other therapies will need to be determined.

The primary systemic vasculitides are idiopathic disorders characterized by the inflammatory destruction of blood vessel walls. Many of these disorders are treated with high-dose glucocorticoids and cytotoxic agents which, while effective, are associated with substantial morbidity, particularly for patients who experience recurrent flares requiring chronic therapy. Therefore, attention has turned towards biologic therapies that abrogate specific elements in the inflammatory cascade. Tumor necrosis factor-α is a cytokine that is central to systemic inflammation in many diseases. This article will review the role played by tumor necrosis factor-α in the pathogenesis of systemic vasculitis, and attempt to define a role for blockade of tumor necrosis factor-α in the treatment of patients with these diseases.

Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CSS) are grouped together under the term ‘Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis’ (AAV). Recently, the British Society for Rheumatology and the European League Against Rheumatism have individually published recommendations on the management of AAV. This paper reviews the two recommendations, and the recent advances in the management of AAV. Pattern recognition and clinical suspicion remains the cornerstone for an early diagnosis. The combination of cyclophosphamide and glucocorticoid is the standard of therapy for remission induction. Patients with less severe disease can be treated effectively with less toxic therapies. There is almost no reason to routinely continue using cyclophosphamide beyond 6 months. Long-term remission maintenance is possible with a variety of immunomodulating agents. With increasing survival, the recognition and management of complications like cardiovascular disease, renal failure, malignancy requires long-term follow up and regular screening.

Giant-cell arteritis (GCA) and Takayasu's arteritis (TAK) are chronic and relapsing inflammatory diseases involving large and medium sized arteries. While symptoms derived from large-vessel involvement characterize TAK clinical presentation, cranial symptoms and complications usually dominate the clinical picture of GCA. However, delayed consequences of large-artery involvement are being increasingly recognized. Glucocorticoids are the mainstay of treatment for both conditions but flares and relapses are common when glucocorticoids are tapered or discontinued and adverse effects are frequent. Methotrexate has shown modest efficacy as glucocorticoid-sparing agent in GCA whereas infliximab did not demonstrate benefit in a randomized clinical trial. Adjuvant treatment for TAK is only supported by open-label trials and observational studies and small series, and methotrexate is the most widely used immunosuppressive agent. Infliximab shows promise for refractory/relapsing TAK as supported by an open label study with long-term follow up. Abatacept is currently being tested for both diseases in a randomized controlled trial. Other investigational agents in the horizon such as rituximab and tocilizumab have been anecdotally used but their efficacy needs to be confirmed. Revascularization procedures, mainly angioplasty, play a crucial role in the management of patients with TAK.

Several viruses have been suspected of causing or triggering vasculitis, with hepatitis B virus-related polyarteritis nodosa (HBV-PAN) and hepatitis C virus-related mixed cryoglobulinemic vasculitis (HCV-MCV) having the best demonstrated and confident proof for a causal link with viruses. Human immunodeficiency virus, erythrovirus B19, cytomegalovirus, varicella-zoster virus or human T-cell lymphotropic virus-1 can also induce mainly localized vasculitis. Conversely, no strong evidence indicates that viruses are implicated in the pathogenesis of other primary systemic vasculitides, like Kawasaki or Behcet's diseases, or granulomatosis with polyangiitis (Wegener's). Treatment for all these virus-associated vasculitides should be two-pronged: one to control and clear the viral infection, using antiviral drugs; the other to rapidly control the clinical manifestations of vasculitis. Management of this second concomitant therapy is more delicate. It can rely on plasma exchange to clear immune complexes in HBV-PAN or rituximab in HCV-MCV, but sometimes it must include short durations of corticosteroids, and cytotoxic agents for most severe cases, both of which are potentially deleterious because they can hamper virus clearance and delay seroconversion.

Chronic Granulomatous Disease (CGD) is a rare inherited primary immunodeficiency, characterized by recurrent bacterial and fungal infection. The outlook for patients with CGD has improved since it was first recognized in the 1950s but individuals still suffer significant morbidity and reduced life expectancy. Recent developments clarifying the role of neutrophil granule proteases and neutrophil extracellular traps in microorganism killing have contributed to our understanding of the susceptibility of CGD patients to infection. There have been developments in our understanding of the inflammatory component of CGD, in particular the similarities between CGD bowel disease and Crohn's disease. There have been advances in treatment, in particular new antifungal agents. Large epidemiological studies have highlighted the many problems CGD patients suffer. With improved survival inflammatory complications of CGD have become more problematic, particularly gastro-intestinal disease. Poor growth is common. There have also been concerns about cognitive deficits in those with CGD. Hematopoeitic stem cell transplant provides complete cure and gene therapy holds hope for the future despite its current limitations. However, these curative measures are not without risk and families are often left with a dilemma regarding whether to opt for curative measures or remain on conservative management.