Systemic Vasculitis: State of the Art and Emerging Concepts

Nicolò Pipitone; Carlo Salvarani


Curr Opin Rheumatol. 2006;18(1):1-2. 

The recognition of vasculitis as a distinct clinical entity goes back about 150 years,[1] but systemic vasculitides still remain elusive from many standpoints. Joint efforts have generated more accurate classification schemes,[2,3,4] provided new diagnostic tools,[5] and defined better treatment strategies tailored to disease severity.[6] These advances have undoubtedly translated into a significant improvement of the prognosis; however, vasculitis continues to pose many challenges, and research into its etiopathogenesis, clinical manifestations, and therapy remains in full swing.

This issue of Current Opinion in Rheumatology comprises eight papers, starting with a review by our group aimed at updating clinicians on the recent advances in the therapeutic management of Adamantiades-Behçet's disease. We share the view that significant clinical responses can now be achieved with biologic agents in patients with Behçet's disease resistant to conventional treatment, particularly in those with inflammatory eye disease. At the same time, we feel it is apposite to caution that disease subsets characterized by severe morbidity and mortality, such as vasculo- and neuro-Behçet, remain difficult to treat. Given the rarity of such subsets, multicenter studies using uniform assessment criteria are needed to recruit sufficiently large numbers of patients and arrive at confident conclusions.

Six of the remaining topics that feature in this issue of Current Opinion in Rheumatology provide an updated and comprehensive review of other important vasculitides, while one contribution gives excellent coverage of the much-debated link between infections and vasculitis. All these contributions have been made by outstanding authors with unique expertise in the field they have reviewed. Taken together, these reports clearly convey the impression of the heterogeneity that characterizes vasculitis, which accounts for at least part of the difficulty encountered in clarifying disease etiopathogenesis and devising therapeutic strategies.

The gold standard for the initial treatment of Wegener's granulomatosis is a combination of glucocorticoids and cyclophosphamide. However, over time, different therapeutic schemes have been tried in an attempt to minimize cyclophosphamide-associated toxicity. Dr Hellmich and colleagues discuss in their excellent paper both standardized and alternative strategies that have been proposed for remission induction and in the maintenance phase of the disease. While the concept of aggressive initial treatment of life- or organ-threatening disease with cyclophosphamide and glucocorticoids remains unquestioned, there is now evidence suggesting that in less severe cases and in the maintenance phase alternative regimens can be used without jeopardizing clinical efficacy. Another important point that emerges from the studies reviewed by the authors is the need for adequate maintenance therapy due to the high rates of relapse after treatment withdrawal.

Abdominal aortic aneurysms are found in approximately 3% of adults aged 50 or over, and may be fraught by a number of complications including rupture, with a substantial risk of death. The presence of histologically detectable inflammation in a number of abdominal aortic aneurysms has been known for a while, but the common interpretation was to consider it an excessive local response to atherosclerotic plaque antigens. Contrary to this view, Professor Schirmer and his coworkers provide an authoritative review of the histological, immunological, genetical, and functional-imaging studies that support the hypothesis of a 'primary' immune-mediated pathogenesis for a subset of abdominal aortic aneurysms. The inflammatory nature of this subset justifies its inclusion in this issue of Current Opinion in Rheumatology and possibly in the classification of large-vessel vasculitis, as we have proposed elsewhere.[7] Finally, an important therapeutic corollary is that inflammatory abdominal aortic aneurysms may benefit from immunosuppressive treatment, although data from human studies are still lacking.

Giant cell arteritis is also known as 'cranial arteritis' or 'temporal arteritis' because it typically affects the cranial branches of the arteries arising from the aortic arch, particularly the temporal arteries. However, involvement of large vessels can also occur, leading to complications such as thoracic and abdominal aortic aneurysms. In this issue, Dr Matteson and Dr Bongartz from the Mayo Clinic describe the full spectrum of large artery involvement in giant cell arteritis, the prevalence of which they estimate as being as high as one-quarter of all cases. Since such involvement is clinically silent in the early stages, the authors emphasize that imaging studies are required for a precocious diagnosis and avoidance of future complications. The role of conventional X-rays, Doppler ultrasound, computed tomography, and magnetic resonance imaging/angiography, as well as of positron emission tomography with 18F-fluorodeoxyglucose, in the diagnosis and in monitoring response to treatment is thoroughly discussed. The lesson from this excellent review is obvious: no marks for missing large artery involvement in giant cell arteritis!

Cryoglobulinemic vasculitis is an immune-complex-mediated small-vessel vasculitis very often, although not invariably, related to hepatitis C virus infection. Given the spread of the hepatitis C virus infection worldwide, cryoglobulinemic vasculitis is increasingly becoming one of the most common forms of vasculitis and has already been a topic of previous issues of Current Opinion in Rheumatology. In the current issue, Professor Ferri and Professor Mascia, who have played a prime role in investigating cryoglobulinemic vasculitis, comprehensively review the most relevant advances in its pathogenesis and treatment. The authors' characterization of the hepatitis C virus-negative variant of the condition as well as of cryoglobulinemic vasculitis overlapping with other disorders rounds off nicely the description of hepatitis C virus-related cryoglobulinemic vasculitis.

Thromboangiitis obliterans, eponymically known as Buerger's disease, stands out among the vasculitides because of its very strong association with tobacco use, the paucity of inflammatory features, and its specific treatment (discontinuation of smoking). Thromboangiitis obliterans is conspicuously rare, which has hampered studies into its pathogenesis. However, while relatively little progress has been made in the understanding of this disease since Buerger's original report, there are few, but promising, therapeutic approaches in the offing for those patients with critical ischemia in spite of smoking cessation. In this issue, Dr Olin and Dr Shih provide a very clear and updated review of thromboangiitis obliterans spanning all relevant disease aspects, from pathogenesis to treatment. Of particular interest is their discussion of therapeutic angiogenesis using intramuscular vascular endothelium growth factor gene therapy and the suggestion of a possible role for the endothelin antagonist bosentan in the light of the raised concentrations of the vasoconstrictor endothelin-I in patients with active thromboangiitis obliterans.

Kawasaki disease is the most common vasculitis in childhood and the leading cause of acquired heart disease in developed countries, with coronary artery aneurysms occurring in up to 5% of patients in spite of treatment. Dr Falcini highlights in her comprehensive review all major advances made in the etiology, pathogenesis, diagnostic procedures, and therapy of Kawasaki disease. Controversial and emerging issues, such as the recognition of atypical and incomplete disease forms, and the role of newer imaging techniques in detection and follow-up of heart involvement, are clearly laid out and discussed. Another point of this review that clinicians will find very valuable is the inclusion of suggestions for the treatment of resistant cases.

Seven years have elapsed since the link between infectious agents and vasculitis was last specifically reviewed in Current Opinion in Rheumatology.[8] The authoritative contribution by Dr Rodriguez-Pla and Dr Stone published in this issue is therefore a welcome, eagerly awaited, update on this topic. Indeed, few issues have attracted so much attention and yielded such conflicting results as research into infectious causes of vasculitis and other immune-mediated disorders. The main reason lies most probably in the very complex way in which microorganisms interact with their hosts, but also in the difficulty of telling apart pathogens from innocent bystanders, which has further been increased by the availability of highly sensitive molecular biology techniques. However, while many of the purported links between infectious agents and vasculitides remain speculative (with few notable exceptions, such as the association of hepatitis B or C with their respective vasculitic syndromes), evidence mapping infectious agents to vasculitis continues to accrue. The authors have succeeded in providing a very well balanced update on this moot topic. Recent advances in etiology, such as the isolation of a novel virus (New Haven coronavirus) that has been implicated in the genesis of Kawasaki disease, but also new pathogenetic hypotheses, such as the 'autoantigen complementarity' linking infections to antineutrophil cytoplasmic autoantibody synthesis, have been carefully reviewed. To the researcher, this paper will no doubt give much food for thought and hopefully many insights for future work.


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