Current Immunology Reviews (v.7, #4)

Wegener’s granulomatosis (WG) was described in 1936 [1], Churg-Strauss syndrome (CSS) in 1951 [2], and microscopicpolyangiitis (MPA) was formally recognized in 1994 [3]. These three conditions have been linked under the umbrella term ofANCA associated vasculitis (AAV) due to their association with antibodies directed against antigens in the neutrophilcytoplasm (ANCA). All three conditions produce necrotising vasculitis of medium and small vessels with differingpredilections to various organs. Although these conditions have been recognized since the 1930’s, the first clinical trial was notpublished till 1983. Fauci et al. shared their experience of using open label, uncontrolled oral cyclophosphamide andglucocorticoid combination therapy in patients with WG [4]. That paper described 85 patients recruited in one centre over 21years. 27 years later, two randomised clinical trials were published in the same week [5-6]. Between the two, the papersdescribed 245 patients with WG or MPA recruited over 4 years and followed up for predefined durations in 17 centres acrossthe world. Compared to the first 60 years of WG, our understanding and thus our methodology of investigating potentialtherapies for these conditions has changed dramatically. In the last decade there have been 12 randomised controlled trials inpatients with AAV (Table 1).It has taken a huge amount of co-ordinated effort to overcome the challenges of studying these relatively rare conditions. Tillthe Chapel Hill Consensus conference (CHCC), MPA had not been formally defined, although its existence distinct frompolyarteritis nodosa (PAN) had been recognised [3]. Prior to the CHCC definitions it was common to club together MPA andeven CSS under the umbrella of ‘PAN’. Although these definitions are not diagnostic, they have been of value in identifyinghomogenous populations for clinical trials. This in turn led to the recognition that the different AAV may have different clinicaloutcomes [7].The first clinical trials in AAV were single centre studies. This often meant that the studies were either underpowered, took along time to recruit adequate numbers of patients, or mixed the differing vasculitis syndromes. All of these problems oftenmade the data difficult to interpret. This problem brought together vasculitis researchers to form research groups. The FrenchVasculitis Group (FVSG), the European Vasculitis Study Group (EUVAS) and the American Vasculitis Clinical ResearchConsortium (VCRC) were born out of efforts to conduct meaningful vasculitis research. Of the 12 RCT’s conducted in the lastdecade (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 generalconsensus 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. Variousclinical tools have been used to measure disease activity, but the one that has been accepted as consensus has been theBirmingham Vasculitis Activity Score (BVAS) [10]. Of the 12 RCT’s in the past decade, 9 have used different versions of theBVAS as the outcome measure, and the other 3 applied the BVAS retrospectively as they had started recruiting patients prior tothe validation of the first version of BVAS. The use of a single validated clinical tool to measure disease activity in all theclinical trials has made it possible to compare outcomes from different clinical trials...............

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

The Need for Diagnostic Criteria in Systemic Vasculitis by Ravi Suppiah, Joanna Robson, Neil Basu, Raashid Luqmani (394-401).
There are currently no diagnostic criteria for the systemic vasculitides. Due to the heterogeneous and nonspecific manner that vasculitis can present there is often a delay in diagnosis which translates to increase morbidity andmortality. The current disease definitions and classification criteria are often misapplied as diagnostic criteria, butevaluation of this has shown that they do not perform satisfactorily for this purpose. We discuss the CHCC definitions, theACR classification criteria and the EMEA algorithm which is needed to bridge the inconsistency between the two. Wealso evaluate the FVSG proposal for polyarteritis nodosa, and attempts of the Behcet’s disease community to developdiagnostic criteria. We provide a brief summary of how a diagnosis of vasculitis is currently made, describe howincreased understanding of disease mechanisms has identified biomarkers which aid diagnosis, and describe howclinically 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 thesedisorders 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-associatedvasculitides (AAV), in particular granulomatosis with polyangiitis and microscopic polyangiitis. This close associationsuggests 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. Longitudinalobservations 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 anddisease activity of the AAV, but others found not. This could be due to methodological shortcomings but also to inherentdifferences in pathogenicity between MPO-ANCA and PR3-ANCA. More studies are needed to solve this question.

B Cell Depletion in Systemic Vasculitis by Rona M. Smith, David R.W. Jayne (415-422).
The important role of B cells in the pathogenesis of systemic vasculitis has become increasingly clear overrecent years. B cell directed therapies offer an exciting new approach to the treatment of these conditions, in which therehas been little change in the options available to managing clinicians since the advent of traditional immunosuppressivetherapy. The introduction of conventional immunosuppression has transformed survival in systemic vasculitis, particularlyANCA-associated vasculitis, but at the expense of significant toxicity, and with suboptimal efficacy. B cell therapies offerthe possibility of targeted, individually tailored immunotherapy, which by improving efficacy, and reducing toxicity willimprove clinical outcomes in systemic vasculitis. However, the heterogeneity of vasculitic syndromes suggests that oneagent is unlikely to be effective in all situations. The precise indications and optimal combination of B cell directed withother therapies will need to be determined.

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

Management of Antineutrophil Cytoplasmic Antibody Associated Vasculitis by Elena Nikiphorou, Chetan Mukhtyar (429-434).
Wegener’s granulomatosis (WG), microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CSS) aregrouped 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 publishedrecommendations on the management of AAV. This paper reviews the two recommendations, and the recent advances inthe management of AAV. Pattern recognition and clinical suspicion remains the cornerstone for an early diagnosis. Thecombination of cyclophosphamide and glucocorticoid is the standard of therapy for remission induction. Patients with lesssevere disease can be treated effectively with less toxic therapies. There is almost no reason to routinely continue usingcyclophosphamide beyond 6 months. Long-term remission maintenance is possible with a variety of immunomodulatingagents. With increasing survival, the recognition and management of complications like cardiovascular disease, renalfailure, malignancy requires long-term follow up and regular screening.

Treatment of Large Vessel Vasculitis by Marco A. Alba, Georgina Espigol-Frigole, Montserrat Butjosa, Sergio Prieto-Gonzalez, Ana Garcia-Martinez, Jose Hernandez-Rodriguez, Maria C. Cid (435-442).
Giant-cell arteritis (GCA) and Takayasu’s arteritis (TAK) are chronic and relapsing inflammatory diseasesinvolving large and medium sized arteries. While symptoms derived from large-vessel involvement characterize TAKclinical 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 oftreatment for both conditions but flares and relapses are common when glucocorticoids are tapered or discontinued andadverse effects are frequent. Methotrexate has shown modest efficacy as glucocorticoid-sparing agent in GCA whereasinfliximab did not demonstrate benefit in a randomized clinical trial. Adjuvant treatment for TAK is only supported byopen-label trials and observational studies and small series, and methotrexate is the most widely used immunosuppressiveagent. Infliximab shows promise for refractory/relapsing TAK as supported by an open label study with long-term followup. Abatacept is currently being tested for both diseases in a randomized controlled trial. Other investigational agents inthe 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.

Virus-Associated Vasculitides by Christian Pagnoux, David Saadoun (443-451).
Several viruses have been suspected of causing or triggering vasculitis, with hepatitis B virus-relatedpolyarteritis nodosa (HBV-PAN) and hepatitis C virus-related mixed cryoglobulinemic vasculitis (HCV-MCV) having thebest 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 systemicvasculitides, like Kawasaki or Behcet’s diseases, or granulomatosis with polyangiitis (Wegener’s). Treatment for all thesevirus-associated vasculitides should be two-pronged: one to control and clear the viral infection, using antiviral drugs; theother to rapidly control the clinical manifestations of vasculitis. Management of this second concomitant therapy is moredelicate. It can rely on plasma exchange to clear immune complexes in HBV-PAN or rituximab in HCV-MCV, butsometimes it must include short durations of corticosteroids, and cytotoxic agents for most severe cases, both of which arepotentially deleterious because they can hamper virus clearance and delay seroconversion.

Recent Advances in Understanding and Management of Chronic Granulomatous Disease by Theresa S. Cole, Andrew J. Cant, Andrew R. Gennery (452-459).
Chronic Granulomatous Disease (CGD) is a rare inherited primary immunodeficiency, characterized byrecurrent bacterial and fungal infection. The outlook for patients with CGD has improved since it was first recognized inthe 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 microorganismkilling have contributed to our understanding of the susceptibility of CGD patients to infection. There have beendevelopments in our understanding of the inflammatory component of CGD, in particular the similarities between CGDbowel disease and Crohn’s disease. There have been advances in treatment, in particular new antifungal agents. Largeepidemiological studies have highlighted the many problems CGD patients suffer. With improved survival inflammatorycomplications 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 currentlimitations. However, these curative measures are not without risk and families are often left with a dilemma regardingwhether to opt for curative measures or remain on conservative management.