We open this year's vasculitis update with two mainly pediatric forms of systemic vasculitis. With our ever expanding use of genetic analysis technology, there has been much interest in bi-allelic mutations in the adenosine deaminase 2 (ADA 2) gene in many forms of vasculitis. We learn from Sahin et al. (pp. 3–14) since the initial description only 5 years ago there has truly been a burst of related publications about the broad spectrum clinical phenotypes, including vasculitis. As is true for the main bulk of genetics-disease information at hand the causal aspect of these mutations are to be further pursued. In this line we are unaware of studies utilizing the recently much in vogue Mendelian randomization approach to causality in ADA 2 gene association work. We learn that the state of the art treatment for this group of diseases is tumor necrosis factor (TNF) inhibitor use. For the resistant patients, hematopoietic stem cell transplantation (HSCT) is a cumbersome but a very successful treatment modality. According to one major study  all 14 patients were cured, six of whom also had vasculitis. This observation surely has important implication for causality as the patients got mutation free stem cells and got better. The devil's advocate on the other hand can point out that the HSCT procedure itself involves immense myelo-immunosuppresion and could be another cause behind the successful treatment. Furthermore patients with identical mutations can present with marked differences in disease expression . In addition, there is lack of information about the fate of homo or compound heterozygotes in the general population of this autosomal recessive condition.
Kawasaki disease is another mainly childhood vasculitis much better known and understood. Marrani et al. (pp. 15–20) first update us to the fact there has recently been a serious attempt to formulate mainly a set of genetic criteria based on polymorphism associations. Although our authors underline that the diagnosis is still clinical they seem to be hopeful. With more data, the referred proposed criteria might eventually be commonly used. We should, however, have to remind ourselves that these criteria have just over 90% specificity and the said polymorphisms show marked ethnic variability. Given these, in a rare condition like Kawasaki disease perhaps the pediatricians should perhaps aim for differing diagnostic criteria at different geographies, perhaps even further stratified as to subspecialty . We also find out from Marrani et al. that perhaps the traditional Aspirin as the first drug might be phasing out being replaced by intravenous immunoglobulin and TNF inhibitor use.
The update of vasculitis associated primary Sjögren's syndrome (pSS) by one of, if not the most, Sgögren's dedicated research groups around the globe opens with the assertion that it is the cryoglobulinemic vasculitis that makes up the majority of cases of vasculitis in pSS (pp. 21–28). More infrequently antineutrophil cytoplasmic antibody associated vasculitis and even large vessel vasculitis has also been described, the last form exclusively from the Far East . In this line, while large vessel vasculitides are mainly T cell diseases a recent histology study revealed massive B cell infiltrates in the surgical specimens in patients in the aortic walls of patients who had aortitis . We can predict that we will hear more about this large vessel connection with pSS in the future.
When we talk about vasculitis we, rightfully, almost always consider arterial disease. The Seyahi chapter (pp. 29–34) reminds us of the importance of venous inflammation. In this line, we are reminded that Behçet syndrome is the prototype and ulcerative colitis comes second. It is well recognized that many different forms of venous vascular disease, ranging from dural sinus thrombi to superficial thrombophlebitis show clinical associations in disease expression of Behçet syndrome . Two groups [7,8] have recently shown that vein wall thickness is increased among Behçet syndrome patients with no apparent vascular involvement. Seyahi, by a critical literature review also reminds us that venous vasculitis/vasculopathy is also a primary disease in eye, CNS disease even when it is parenchymal, in nodular lesions of the skin and colonic disease. Thus it is apparent that venous vasculitis/vasculopathy in Behçet syndrome deserves a closer scrutiny. The main disease in pSS, has for some time been summarized as an ‘an autoimmune epithelitis’ (pp.21–28). In this line we might consider beginning to call Behçet syndrome as primarily an ‘endothelitis’ while we remain doubtful of the ‘autoimmune’ designation .
In the next chapter Y. Yazici (pp. 35–40) updates the current management of Behçet syndrome mainly based on the 2018 European League Against Rheumatism recommendations . Of the new agents in management, aprelimast, seems to be a promising agent by several accounts. It has anti-inflammatory activity both directly through blocking the phosphodiesterase-4 pathway and by enhancing the production interleukin 10, an anti-inflammatory cytokine, the production of which is suppressed in Behçet syndrome. Another positive point about this medication is that two double blind studies, both showing favorable results are available [10,11]. We still wait for formal data on its possible effects on lesions of Behçet syndrome other than oral ulcers. Finally, we have to underline here the paucity of randomized controlled trials, especially with biologics in Behçet syndrome. There is little doubt that they are very useful especially in managing eye disease while we still do not know for how long to use them. In this line, as pointed out by the author formal withdrawal studies would, for some reason not very popular in the management of any rheumatological disease, would be quite useful.
Hajj-Ali and Calabrese remind us that the diagnosis of central nervous system vasculitis (CNS-V) remains very challenging (pp. 47–52). The so called primary CNS-V is quite rare and even in instances in which we have histologic evidence of vessel wall damage the primary diagnosis can still be an infection or a neoplasm. On the other hand, a wider use of the newer diagnostic methods in imaging like the ultra wide imaging of the retina and high resolution magnetic resonance imaging should improve our diagnostic acumen. The same holds true for metagenomic next-generation sequencing for infectious agents . The chapter closes with reminding us the presence of a new concept in nosological clustering, the so named BEE (brain, eye and ear) syndrome . It is proposed that the presence of this cluster would help us in the correct diagnosis of CNS-V. We are bit skeptical about the possible clinical utility of this proposal which encompasses a very varying spectrum of entities ranging from Susac and Behçet syndromes to systemic lupus and sarcoidosis.
In line with the new concept of BEE syndrome the next chapter by Rahne et al. is about vasculitis and the ear (pp. 000–000). We are first usefully reminded that the main symptom is hearing loss and there are three main leading pathologies, sensorineural, conductive, and combined. In vasculitides effecting the ear the sensorineural problems dominate. In this context we learn that granulomatosis with polyangiitis (Wegener's) is an important exception in which hearing loss is found in about 1/5th of the patients and the problem is the conductive disease.
This year's update of vasculitides ends with a useful chapter on vasculitis associated with immune checkpoint inhibitors (ICI). Although vasculitis is a rare complication of ICI we see an increasing number of patients by the virtue of the fact that ICI are rather successfully, and thus increasingly used, in oncology. Sandigursky et al. (pp. 53–56) not only give us an update on the vasculitic adverse effects of ICI, importantly not to be confused with paraneoplastic vasculitis, they present a very readable account of how these agents work and cause adverse effects in general.
Financial support and sponsorship
Conflicts of interest
Y.Y. – disclosures: consultant: Celgene, BMS, Sanofi;
research support: Celgene, BMS, Genentech. H.Y. has no conflicts of interest.
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