Vasculitis Pathogenesis: Can We Talk About Precision Medicine?
- 1Division of Rheumatology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey
- 2Division of Rheumatology, Department of Pediatrics, University of Health Sciences, Ankara Training and Research Hospital, Ankara, Turkey
Precision medicine is designing the medical care by taking into account the individual variability for each person. We have tried to address whether the existing data may guide precision medicine in primary systemic vasculitides (PSV). We have reviewed genome-wide association studies (GWAS) data, lessons from monogenic mimics of these diseases, and biomarker studies in immunoglobulin A vasculitis/Henoch–Schönlein purpura, Kawasaki disease, anti-neutrophil cytoplasmic antibody-associated vasculitis, polyarteritis nodosa (PAN), Takayasu arteritis, and Behçet’s disease (BD). GWAS provide insights about the pathogenesis of PSV while whole exome sequencing studies lead to discovery of monogenic vasculitides, phenotype of which could mimic other types of vasculitis such as PAN and BD. Monogenic vasculitides form a subgroup of vasculitis which are caused by single gene alterations and discovery of these diseases has enabled more specific therapies in these patients. With increasing number of studies on biomarkers, new targets for treatment appear and better and structured follow-up of PSV patients will become possible. Proteomics and metabolomics studies are required to better categorize our patients with PSV so that we can manage them appropriately and offer more targeted therapy.
Precision medicine is defined as designing the medical care for each person with optimum efficiency in prevention and treatment by considering the individual variability in genes, environment, and life style (1). Precision medicine enables to translate benchside knowledge to bedside and provide “targeted” treatment for the patient. Genetic or molecular profiling of patients is very important for precision medicine; however, there are limited data in primary systemic vasculitides (PSV).
Primary systemic vasculitides are heterogeneous. Since these are mostly rare diseases, we lack the vast translational medicine data we have in common diseases such as rheumatoid arthritis. Furthermore, controlled studies in PSV might not reflect the real-life scenarios. Thus, it is important to tailor treatment according to each patient instead of applying general recommendations which are based on controlled studies.
Thanks to improved and cheaper genomic techniques, we have gathered important data that may be used on the bedside. Genetic studies including mainly genome-wide association studies (GWAS) and whole exome sequencing studies have led to important discoveries in disease pathogenesis of PSV. However, we lack pharmacogenomics studies. We are also in need of more biomarker studies to provide novel candidate targets for therapy and help us to predict prognosis. Predicting poor prognosis or high relapse rate through biomarkers could guide physicians to tailor treatment according to the patient. More intensified immunosuppressive therapy could be required in patients with poor prognosis while longer maintenance therapy could prevent relapses in patients with high relapse risk.
In this article, we review the GWAS results, monogenic vasculitis, and existing biomarkers, which have implications on precision medicine in treatment of PSV. We have mainly focused on immunoglobulin A vasculitis/Henoch–Schönlein purpura (IgAV/HSP), Kawasaki disease (KD), polyarteritis nodosa (PAN), anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Takayasu arteritis (TA), and Behçet’s disease (BD).
What We Have Learned from GWAS in PSV
Genome-wide association studies provide an important step forward in our understanding of vasculitis pathogenesis. Focusing on subgroups of patients with PSV will provide further insight while profiling patients to tailor treatment individually. There are several GWAS in patients with different types of PSV such as IgAV/HSP, KD, AAV, TA, and BD (Table 1). There is no GWAS in PAN patients at present.
Immunoglobulin A Vasculitis/Henoch–Schönlein Purpura
In the GWAS of 285 Spanish patients with IgAV/HSP, Lopez-Mejias et al. observed p values of potential relevance (below genome-wide significance) for the positions 11 and 13 of HLA-DRB1 (2). This study implicated HLA Class II in the pathogenesis of the disease. Larger multinational studies may be needed to confirm this association and look for associations with certain cytokines and aberrant glycosylation of IgA1. Investigation of the association of the IgAV/HSP kidney disease with IgA nephropathy in a combined study will also be of major interest, since the IgA nephropathy has been claimed to be in the spectrum of the disease, lacking systemic features. So far, the GWAS in IgAV/HSP has not had a substantial offer to precision medicine.
There are more than 10 GWAS performed in KD (3–16). The results of these GWAS may affect our medical practice since these help us to define KD patients who are at risk of developing intravenous immunoglobulin (IVIG) resistance and/or coronary involvement. The susceptibility genes associated with the development and severity of coronary involvement were mainly identified as KCNN2, TIAM1, NEBL, TUBA3C, PELI1, and PLCB4/PLCB1 (3, 6, 7, 13, 14). Shimizu et al. performed a pathway-based association analysis on a GWAS data set to identify risk alleles for coronary artery abnormalities in KD (17). They demonstrated susceptibility variants in the SLC8A1 calcium signaling pathway which were associated with development of KD and coronary artery abnormalities (17). Their results suggested this pathway as a therapeutic target supporting the use of calcineurin inhibitors in acute KD.
Recently, Kwon et al. have performed an IVIG-response stratified GWAS to search for IVIG-response-specific genetic variants associated with KD (11). They have identified an intronic single-nucleotide polymorphism (SNP) in BCL2L11 which was significantly associated with KD in IVIG responders but not in non-responders (11). In the first weighted genetic risk score study based on a GWAS in KD, Kuo et al. have presented the predictive model integrating the additive effects of 11 SNPs to provide a prediction for IVIG responsiveness (18). Thus these studies may be regarded to have an effect on precision medicine since they may define how we treat these patients in the coming days.
On the other hand, other GWAS have identified susceptibility genes associated with KD (mainly HLA, CD40, BLK, FCGR2A, NMNAT2, HCP5, COPB2, ERAP1, NAALADL2, ZFHX3, NFKBIL1, LTA, DAB1, IGHV) (4, 5, 9, 10, 12, 15, 16).
In a study of replication and meta-analysis of GWAS in KD, Chang et al. identified risk alleles confirming the importance of B lymphoid tyrosine kinase (BLK) which suggested a role for B-cell-mediated therapies in KD (19). Lv et al. reviewed the genes which had statistically significant associations with KD, from candidate gene studies and GWAS (20). They showed that cellular calcium ion hemostasis, immune and inflammatory responses were the main functional categories representing associated genes (20).
The GWAS of AAV has indeed provided quite important data on the genetic disparities of these diseases. In the first GWAS in AAV, Lyons et al. demonstrated that granulomatous polyangiitis (GPA, Wegener’s) and microscopic polyangiitis were genetically distinct diseases and anti-myeloperoxidase ANCA was associated with HLA-DQ while anti-proteinase 3 (anti-PR3) ANCA was associated with HLA-DP, SERPINA1, and PRTN3 (21). This study has revealed the antigenic specificity of ANCA forms the strongest associations in AAV. Xie et al. identified risk variants for GPA in SEMA6A and HLADP (22). Thus, these GWAS have not only had an impact on our vasculitis classification but also provided us data on how to predict the course in these patients.
On the other hand, Merkel et al. identified genome-wide significant associations for AAV at the HLA-DPB1, SERPINA1, PTPN22, and PRTN3 loci with the largest effect coming from HLA-DPB1 polymorphisms (23).
In a GWAS of TA patients from Turkey and North America, Saruhan-Direskeneli et al. identified susceptibility loci as HLA-B/MICA, HLA-DQB1/HLA-DRB1, and FCGR2A/FCGR3A (24). They also identified additional association effects of PSMG1, IL12, and IL23 that could not reach genome-wide significance. The association with IL12B variants were confirmed in Japanese TA patients in a genome scanning study (25). In the most recent GWAS of TA, Renauer et al. identified susceptibility variations for TA at IL6, RPS9/LILRB3, and an intergenic locus on chromosome 21q22 (26). Two of these loci, IL6 and RPS9/LILRB3 have roles in immunoregulatory pathways which could enlighten the immunopathogenesis of TA. This may be reflecting our bedside experience for the use of anti-interleukin-6 (IL-6) in TA patients and thus serve as an example for precision medicine if we could have genotyped all these patients. On the other hand, blocking IL-12/IL-23 pathway may also be an option for selected patients.
There are nine GWAS performed in BD patients that have indeed served us to understand the pathogenesis of the disease (27–35). These studies have shown genome-wide significant associations with HLA class I (especially HLA-B51), IL10, IL23R-IL12RB2, ERAP1, STAT4, GIMAP, CCR1, KLRC4, FUT2, IL12A, NAALADL2, YIPF7, KIAA1529, CPVL, LOC100129342, UBASH3B, and UBAC2 regions in BD (27–35). It is important to note that endoplasmic reticulum aminopeptidase 1 (ERAP1) is an endoplasmic reticulum protein functioning as an aminopeptidase trimming peptides for loading onto MHC Class I (36). It has been demonstrated that ERAP1 contributed to the risk for BD in HLA-B51 positive individuals (31). The variants identified in BD GWAS suggest defects in pathways of adaptive and innate immune responses, sensing/processing of microbial and danger signals, and inflammatory pathways shared with spondyloarthropathies (37). These studies have suggested that the improper folding of HLA-B51 is to trigger endoplasmic reticulum stress leading to the IL-12/IL-23 pathway activation. Bakir-Gungor et al. performed a pathway analysis using BD GWAS data from two populations and demonstrated that shared pathways were mitogen-activated protein kinase signaling, transforming growth factor β signaling, focal adhesion, extracellular matrix–receptor interaction, complement and coagulation cascades, and proteasome pathways (38). Thus, GWAS in BD have mainly provided us answers for the pathogenesis of the disease. However, blocking IL-12/IL-23 pathway is being considered in light of these findings. Whether the benchside will hold true in vivo remains to be seen.
All these GWAS performed in PSV patients points to certain mechanisms in the pathogenesis. We clearly lack data on pharmacogenomics. And we need larger cohort of patients who are profiled genetically and phenotypically, to identify the pathogenesis and possibly the disease course and highlight treatment options.
Can Monogenic Vasculitides Teach us Anything?
Most of our common rheumatic diseases are multifactorial diseases with the contribution of certain SNPs (as described above) for disease risk. These SNPs have a rather small impact or introduce a small risk factor for the occurrence of that vasculitis. However, in recent years we have become aware of single gene defects that have a major impact in the inflammatory pathway, causing a phenotype often mimicking a well-known vasculitis (39). Description of monogenic vasculitides has provided novel insights into disease pathogenesis and pathways of inflammation in general. On the other hand, they have enabled targeted therapies in these single-gene disorders. Deficiency of adenosine deaminase 2 (DADA2), stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI), and haploinsufficiency of A20 (HA20) are the recently defined monogenic vasculitides. Indeed, the association of monogenic complement deficiencies with systemic lupus erythematosus had taught us the role of complement in lupus pathogenesis. Similarly, the affected pathways in these diseases may enable us to design more targeted therapies in vasculitides. For example, one may need to concentrate more on the nuclear factor-κB (NF-κB) pathway or the role of macrophages.
Deficiency of Adenosine Deaminase 2
Deficiency of adenosine deaminase 2 is associated with CECR1 mutations and causes a PAN-like vasculopathy and autoinflammatory features (40). ADA2 is thought to trigger the macrophages to have an inflammatory phenotype and endothelial integrity is compromised in DADA2 (41). As a result of these, vasculopathy and inflammation occur.
The phenotype mimics PAN with the presence of aneurysms in visceral arteries. Clinical presentation is a spectrum from only cutaneous lesions to full blown systemic disease (40–42). DADA2 patients may also present with only hematological features such as pure red cell anemia (43). Anti-tumor necrosis factor (anti-TNF) drugs are effective in the treatment of patients with vasculitis whereas response to conventional treatment is poor. Hematopoietic stem cell transplantation is needed in severe cases (40, 44, 45). Hematopoietic stem cell transplantation should be especially considered in DADA2 patients with bone marrow failure who display predominant hematological features (46).
STING-Associated Vasculopathy With Onset in Infancy
Stimulator of interferon genes-associated vasculopathy with onset in infancy is a type I interferonopathy caused by gain-of-function mutations in TMEM173 encoding for STING (47). STING hyperfunction results in constitutive transcription of type I interferons (IFNs) which bind to type I IFN receptors and signal through Janus activating kinase/signal transducer and activator of transcription (JAK/STAT) pathway (47, 48).
Phenotype of SAVI patients could resemble GPA with severe cutaneous vasculopathy, pulmonary involvement, and ANCA positivity in some patients (49). Recently, Sanchez et al. have shown improvement in SAVI patients with baricitinib which is a selective JAK1 and JAK2 inhibitor (50).
Haploinsufficiency of A20
Haploinsufficiency of A20 is a recently defined autosomal dominant autoinflammatory syndrome resembling BD, caused by loss-of-function mutations in TNFAIP3 encoding for A20 protein (51). Restriction of A20 function augments NF-κB signaling which makes NF-κB-dependent proinflammatory cytokines such as TNF-α, IFN-γ, IL-17, IL-1β potential targets for treatment in these patients. Around 50 HA20 patients have been reported so far with early-onset recurrent mucosal ulcers resembling BD being the hallmark feature in most (51–61). HA20 is classified as a monogenic vasculitis here since it resembles BD; however, it is important to note that the phenotype is very heterogeneous and it may mimic autoimmune diseases such as systemic lupus erythematosus and autoimmune lymphoproliferative syndrome. Furthermore, the evidence for vasculitis in tissue samples is deficient in most patients (52).
Familial Mediterranean Fever (FMF)-Associated Vasculitides
Familial Mediterranean fever is the most common autoinflammatory disease characterized by fever and polyserositis attacks and caused by MEFV mutations (62). The mutations in this gene are associated with increased IL-1 production. Colchicine is the mainstay of FMF treatment (62). Certain vasculitides are more frequent in FMF patients than normal population (63). The most common vasculitis associated with FMF is IgAV/HSP, present in around 3% of FMF patients (63, 64). Another form of vasculitis is PAN which is also more common among FMF patients when compared to the expected frequency: almost 1% of FMF patients had PAN with distinctive features such as perinephric hematoma, severe myalgia, markedly high acute phase reactants, younger age, and better survival than classic PAN (39, 63, 65). In the eastern Mediterranean where the disease is frequent, physicians should ask for symptoms of FMF in patients with IgAV/HSP and possibly PAN. Concomitant occurrence of BD and FMF was also much higher than expected in several studies and a high frequency of MEFV mutations was reported in BD patients (66–68). In addition, a meta-analysis has confirmed the association between MEFV mutations M694V and M680I with BD (69). Other PSV such as AAV and TA may accompany FMF, as well; however, their association is not as apparent as the aforementioned diseases.
The association of PSV with this monogenic disease affects the way we treat these patients: colchicine needs to be initiated for FMF in addition to the conventional treatment of vasculitis in these patients. Anti-IL-1 therapies could be considered in resistant cases (62).
Biomarkers in PSV
A biomarker is defined as an objectively measured characteristic marker which is evaluated as an indicator of normal biological or pathogenic processes or pharmacological responses to a therapeutic intervention (70). Biomarkers may be important for predicting the tendency to have the disease, disease activity, therapeutic options, disease flare, and disease course. For precision medicine, important biomarkers are the ones which guide us through choosing therapeutic options or determining patients with poor prognosis who need more aggressive treatment. Although there are recent studies addressing novel biomarkers, biomarker-driven treatment algorithms are not available in PSV. Furthermore, it is important to note that most of the existing biomarker studies in PSV involve mainly adult patients. Thus, the rheumatology community needs sophisticated work of proteomics and metabolomics to define the important pathways and biomarkers for our management of the patients. The main biomarkers that serve therapeutic targets in PSV are summarized in Table 2.
Immunoglobulin A Vasculitis/Henoch–Schönlein Purpura
Biomarker studies in IgAV/HSP have generally focused on finding non-invasive markers for diagnosis/prediction of nephritis and renal prognosis. A few studies are present on biomarkers of prognosis for gastrointestinal involvement, as well. Sun et al. have recently identified biomarkers by a combined clinical and metabolomics analysis in children with IgAV/HSP (71). They have shown that (s)-3-hydroxyisobutyric acid, p-Cresol sulfate, and 3-carboxy-4-methyl-5-pentyl-2-furanpropanoic acid were associated with kidney involvement in IgAV/HSP. These biomarkers allowed prediction of IgAV/HSP nephritis with high sensitivity (94.7%) and specificity (80.8%) when combined with D-dimer (71). Berthelot et al. have studied the value of biomarkers for predicting the outcome of IgAV/HSP nephritis in an adult prospective cohort (72). They have demonstrated that serum Gd-IgG1, urinary IgA, IgG, IgM, neutrophil gelatinase-associated lipocalin, IL-1β, IL-6, IL-8, IL-10, IgA-IgG, and IgA-sCD89 complexes were associated with nephritis while urine IgA at disease onset could predict poor renal outcome in IgAV/HSP patients (72). Other biomarkers such as matrix metalloproteinase 9 (MMP-9), red blood cell distribution width, pentraxin 3, alpha-smooth muscle actin, and c-Met were also reported to be associated with the risk of nephritis in IgAV/HSP (73–76). As to the genetic factors, two recent studies have shown the association of inducible nitric oxide synthase (iNOS) gene and IL1β gene polymorphisms with kidney involvement in IgAV/HSP (77, 78). Thus, these biomarkers may guide us in how we manage these patients in the coming days.
Decreased factor XIII activity was suggested as a prognostic biomarker for severe gastrointestinal system involvement in IgAV/HSP patients (79, 80). Administration of factor XIII concentrate lead to improvement of gastrointestinal complaints in anecdotal case reports (80).
Biomarker studies in KD are mainly focused on predicting patients who will not respond to IVIG treatment. A more intensified treatment with corticosteroids along with IVIG could be administered to the patients with high risk of IVIG unresponsiveness. Early use of biologics may also be indicated in selected cases. Elevated levels of IL-17A, IL-10 (81), ferritin (82), tenascin C (83), IL-6, C-reactive protein (CRP), percentage of circulating neutrophils (84), increased QT interval dispersion (85), and increased ratio of CD8+ HLA-DR+ T cells/CD8+ CD69+ T cells (86) are main biomarkers reported to be used for predicting IVIG resistance in KD. Validation studies are required to use these biomarkers in daily clinical practice.
There have been few studies on biomarkers related to disease activity in PAN. Several biomarkers such as D-dimer, anti-moesin antibody, and anti-endothelial antibodies have been associated with disease activity (87–89). However, none of these are currently being used in routine medical practice in the management of patients with PAN.
In AAV, ANCAs are the most commonly studied biomarkers. These are mainly diagnostic biomarkers and their use for monitoring disease activity is controversial. However, recent studies have suggested that especially PR3-ANCAs could be used to predict relapse in AAV (90–94). Besides ANCA, Kemna et al. have demonstrated that galactosylation and sialylation levels of IgG could predict relapse in PR3-AAV patients (95). In the recent targeted proteomics study, Ishizaki et al. have demonstrated the effectiveness of tissue inhibitor of metalloproteinase (TIMP1) as a disease activity marker for AAV and they have identified transketolase and CD92 as novel markers for evaluation of renal involvement and renal outcome in AAV (96). These may serve as valuable markers in our clinical practice. Two different proteomics studies demonstrated that serum proteomic profile differed between active systemic versus remitting patients with GPA (97, 98).
McKinney et al. studied gene-expression-based biomarkers in AAV and demonstrated that the poor diagnostic group were defined mainly by the IL7R pathway and T cell receptor signaling genes which were expressed by T cells (99). Their results also suggested that measuring the expression of only three genes; ITGA2, NOTCH1, and PTPN22 could be used to define prognostic subgroups in AAV. These results raise the prospect of precision medicine in AAV, as the authors have concluded. In another study of the same group on gene-expression biomarkers, they demonstrated an association between T cell exhaustion and poor prognosis in AAV and suggested that this process could be targeted in AAV treatment (100).
As to biomarkers for response to treatment in AAV, Unizony et al. demonstrated that patients with PR3-AAV responded better to rituximab than to traditional induction/maintenance treatment with cyclophosphamide and azathioprine and suggested that an ANCA-based classification might guide immunosuppressive treatment in AAV (101). Haubitz et al. showed that immunosuppressive treatment in AAV changes the urine proteome toward remission (102).
Neutrophil microparticles (NMPs) and neutrophil extracellular traps (NETs) are biomarkers that could be targets for treatment in AAV and maybe other vasculitides as well. NMPs are membrane vesicles that induce endothelial damage in AAV, released from neutrophils upon activation by ANCA (103). Hong et al. have demonstrated more NMPs in the plasma of children with AAV than patients with inactive vasculitis and healthy controls (103). AAV patients with increased NMPs might benefit from plasma exchange therapy (103). In the same lines, endothelial MPs, important biomarkers of endothelial injury, may be important targets to be removed by plasma exchange in AAV (103).
Neutrophil extracellular traps, composed of DNA, histones, and neutrophil proteins, are released by neutrophils under the influence of inflammatory stimuli (104). Kessenbrock et al. reported NET deposition in inflamed kidneys of AAV patients (105) while Wang et al. showed that circulating NETs did not differ between patients with active vasculitis and patients in remission (106). NETs could represent a novel target for therapy in AAV; however, further studies are required to determine the exact role of NETs in AAV pathogenesis.
Recent studies have highlighted the role of complement alternative pathway activation in AAV pathogenesis (107). In a recent randomized trial, Jayne et al. have demonstrated that avacopan, an orally administered selective C5a receptor inhibitor was effective in replacing high-dose corticosteroid treatment in AAV (108).
There are other biomarkers such as macrophage migration inhibitory factor, delta neutrophil index, mean platelet volume, rheumatoid factor, and serum ferritin most of which have been recently reported to be associated with disease activity in AAV (109–113). However, further validation studies are required for these biomarkers to be commonly used while profiling AAV patients with regards to disease course and prognosis.
Biomarker studies in TA are mainly focused on differentiating active disease from inactive disease. Different biomarkers such as erythrocyte sedimentation rate (ESR), CRP, IL-2, IL-3, IL-4, IL-6, IL-8, TNF-α, IFN-γ, MMPs, TIMP1, vascular cell adhesion molecules, RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted), and pentraxin 3 were associated with TA disease activity (114–122); however, none of them is validated for predicting outcome and only ESR and CRP are available in routine clinical practice. Some of the aforementioned biomarkers such as IL-6 and TNF-α serve targets for effective therapies in TA (123, 124). Goel et al. have recently demonstrated that myeloid-related protein 8/14 (MRP8/14) (S100A8/S100A9) levels were higher in patients with active disease than those with stable disease and change in MRP8/14 levels was significantly associated with the disease activity assessed by Indian TA Activity Score (125). Furthermore, MRP8/14 levels decreased significantly in responders during follow-up. They also showed that MRP8/14 was a better disease activity biomarker than ESR and nearly similar to CRP in this aspect in TA (125).
As genetic factors, a recently studied biomarker in TA, is human leukocyte antigen E (126). Goel et al. demonstrated that soluble HLA-E levels increased more frequently in TA patients with a persistently active, relapsing course than those with a persistent stable course (126). HLA-Bw52 was previously shown to be associated with higher incidence of cardiovascular events and poorer prognosis in TA patients (127). Terao et al. showed that combination of SNPs on IL12B and HLA-B52:01 was significantly associated with severity of aortic regurgitation, a severe complication of TA (25).
Imaging modalities such as computed tomography, magnetic resonance imaging, and positron emission tomography are important to detect vasculitic lesions in large vessel vasculitis and in practice are used as outcome tools.
Lots of disease activity biomarkers have been reported in BD. None of these (except ESR and CRP as acute phase reactants) are currently being used in routine clinical practice to profile BD patients. However, several of these biomarkers may be targeted in BD treatment. Sadeghi et al. have recently studied the serum profiles of cytokines in BD patients and demonstrated significant elevation of IL-2 in patients with uveitis (compared to recovered patients or those without uveitis) (128). The authors have thus concluded that IL-2 may be a new target for treatment of refractory BD uveitis. Tulunay et al. demonstrated that JAK1/STAT3 signaling pathway was activated in BD, possibly through activation of Th1/Th17-type cytokines such as IL-2, IL-6, IL-17, IL-23, and IFN-γ (129). They suggested that ustekinumab (anti-IL-12/IL-23) and tofacitinib (inhibiting JAK1/3) could be novel therapeutic options for BD. On the other hand, several genetic associations have also been identified in BD, including mainly the genes encoding for HLA-B51, IL-6, IL-10, IL-1β, IL-12R/IL-23R, intracellular adhesion molecule, nitric oxide, chemokine receptor type 5, toll-like receptors, and fucosyltransferase 2 (130). In the same lines, elevated levels of several proinflammatory cytokines including IL-1, IL-6, IL-17, and IL-23 have been demonstrated in patients with BD (131–137). Some of the pathways including these cytokines have been targeted successfully with biologic drugs such as etanercept (anti-TNF), infliximab (anti-TNF), tocilizumab (anti-IL-6), secukinumab (targeting IL-23/IL-17 pathway), and canakinumab (anti-IL-1) (130, 138).
Precision medicine is our new aim in clinics and translational medicine will surely guide this practice. With the recent genetic studies and promising biomarker discoveries, precision medicine will be possible in PSV. The existing data needs to be confirmed in large, multicenter studies. Further proteomics and metabolomics data enlightening the involved pathways are needed. These further studies are required to profile vasculitis patients better to tailor treatment individually.
EB prepared the first draft of the article. SO made the critical revision of the article. Both authors have seen and approved the final version of the manuscript.
Conflict of Interest Statement
SO is receiving consultancy fees from Novartis and Eczacibasi. EB declares no conflict of interest.
1. NIH. The Definition of Precision Medicine. (2018). Available from: https://ghr.nlm.nih.gov (Accessed: April 26, 2018).
2. Lopez-Mejias R, Carmona FD, Castaneda S, Genre F, Remuzgo-Martinez S, Sevilla-Perez B, et al. A genome-wide association study suggests the HLA Class II region as the major susceptibility locus for IgA vasculitis. Sci Rep (2017) 7(1):5088. doi:10.1038/s41598-017-03915-2
3. Kuo HC, Li SC, Guo MM, Huang YH, Yu HR, Huang FC, et al. Genome-wide association study identifies novel susceptibility genes associated with coronary artery aneurysm formation in Kawasaki disease. PLoS One (2016) 11(5):e0154943. doi:10.1371/journal.pone.0154943
4. Burgner D, Davila S, Breunis WB, Ng SB, Li Y, Bonnard C, et al. A genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki disease. PLoS Genet (2009) 5(1):e1000319. doi:10.1371/journal.pgen.1000319
5. Khor CC, Davila S, Breunis WB, Lee YC, Shimizu C, Wright VJ, et al. Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease. Nat Genet (2011) 43(12):1241–6. doi:10.1038/ng.981
6. Kim JJ, Hong YM, Sohn S, Jang GY, Ha KS, Yun SW, et al. A genome-wide association analysis reveals 1p31 and 2p13.3 as susceptibility loci for Kawasaki disease. Hum Genet (2011) 129(5):487–95. doi:10.1007/s00439-010-0937-x
7. Kim JJ, Park YM, Yoon D, Lee KY, Seob Song M, Doo Lee H, et al. Identification of KCNN2 as a susceptibility locus for coronary artery aneurysms in Kawasaki disease using genome-wide association analysis. J Hum Genet (2013) 58(8):521–5. doi:10.1038/jhg.2013.43
8. Kim JJ, Yun SW, Yu JJ, Yoon KL, Lee KY, Kil HR, et al. Common variants in the CRP promoter are associated with a high C-reactive protein level in Kawasaki disease. Pediatr Cardiol (2015) 36(2):438–44. doi:10.1007/s00246-014-1032-1
9. Kim JJ, Yun SW, Yu JJ, Yoon KL, Lee KY, Kil HR, et al. A genome-wide association analysis identifies NMNAT2 and HCP5 as susceptibility loci for Kawasaki disease. J Hum Genet (2017) 62(12):1023–9. doi:10.1038/jhg.2017.87
10. Kwon YC, Kim JJ, Yun SW, Yu JJ, Yoon KL, Lee KY, et al. Male-specific association of the FCGR2A His167Arg polymorphism with Kawasaki disease. PLoS One (2017) 12(9):e0184248. doi:10.1371/journal.pone.0184248
11. Kwon YC, Kim JJ, Yun SW, Yu JJ, Yoon KL, Lee KY, et al. BCL2L11 is associated with Kawasaki disease in intravenous immunoglobulin responder patients. Circ Genom Precis Med (2018) 11(2):e002020. doi:10.1161/CIRCGEN.117.002020
12. Lee YC, Kuo HC, Chang JS, Chang LY, Huang LM, Chen MR, et al. Two new susceptibility loci for Kawasaki disease identified through genome-wide association analysis. Nat Genet (2012) 44(5):522–5. doi:10.1038/ng.2227
13. Lin MT, Hsu CL, Taiwan Pediatric CVG, Chen PL, Yang WS, Wang JK, et al. A genome-wide association analysis identifies novel susceptibility loci for coronary arterial lesions in patients with Kawasaki disease. Transl Res (2013) 161(6):513–5. doi:10.1016/j.trsl.2013.02.002
14. Lin YJ, Chang JS, Liu X, Tsang H, Chien WK, Chen JH, et al. Genetic variants in PLCB4/PLCB1 as susceptibility loci for coronary artery aneurysm formation in Kawasaki disease in Han Chinese in Taiwan. Sci Rep (2015) 5:14762. doi:10.1038/srep14762
15. Onouchi Y, Ozaki K, Burns JC, Shimizu C, Terai M, Hamada H, et al. A genome-wide association study identifies three new risk loci for Kawasaki disease. Nat Genet (2012) 44(5):517–21. doi:10.1038/ng.2220
16. Tsai FJ, Lee YC, Chang JS, Huang LM, Huang FY, Chiu NC, et al. Identification of novel susceptibility loci for Kawasaki disease in a Han Chinese population by a genome-wide association study. PLoS One (2011) 6(2):e16853. doi:10.1371/journal.pone.0016853
17. Shimizu C, Eleftherohorinou H, Wright VJ, Kim J, Alphonse MP, Perry JC, et al. Genetic variation in the SLC8A1 calcium signaling pathway is associated with susceptibility to Kawasaki disease and coronary artery abnormalities. Circ Cardiovasc Genet (2016) 9(6):559–68. doi:10.1161/CIRCGENETICS.116.001533
18. Kuo HC, Wong HS, Chang WP, Chen BK, Wu MS, Yang KD, et al. Prediction for intravenous immunoglobulin resistance by using weighted genetic risk score identified from genome-wide association study in Kawasaki disease. Circ Cardiovasc Genet (2017) 10(5):e001625. doi:10.1161/CIRCGENETICS.116.001625
19. Chang CJ, Kuo HC, Chang JS, Lee JK, Tsai FJ, Khor CC, et al. Replication and meta-analysis of GWAS identified susceptibility loci in Kawasaki disease confirm the importance of B lymphoid tyrosine kinase (BLK) in disease susceptibility. PLoS One (2013) 8(8):e72037. doi:10.1371/journal.pone.0072037
20. Lv YW, Wang J, Sun L, Zhang JM, Cao L, Ding YY, et al. Understanding the pathogenesis of Kawasaki disease by network and pathway analysis. Comput Math Methods Med (2013) 2013:989307. doi:10.1155/2013/989307
22. Xie G, Roshandel D, Sherva R, Monach PA, Lu EY, Kung T, et al. Association of granulomatosis with polyangiitis (Wegener’s) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis. Arthritis Rheum (2013) 65(9):2457–68. doi:10.1002/art.38036
23. Merkel PA, Xie G, Monach PA, Ji X, Ciavatta DJ, Byun J, et al. Identification of functional and expression polymorphisms associated with risk for antineutrophil cytoplasmic autoantibody-associated vasculitis. Arthritis Rheumatol (2017) 69(5):1054–66. doi:10.1002/art.40034
24. Saruhan-Direskeneli G, Hughes T, Aksu K, Keser G, Coit P, Aydin SZ, et al. Identification of multiple genetic susceptibility loci in Takayasu arteritis. Am J Hum Genet (2013) 93(2):298–305. doi:10.1016/j.ajhg.2013.05.026
25. Terao C, Yoshifuji H, Kimura A, Matsumura T, Ohmura K, Takahashi M, et al. Two susceptibility loci to Takayasu arteritis reveal a synergistic role of the IL12B and HLA-B regions in a Japanese population. Am J Hum Genet (2013) 93(2):289–97. doi:10.1016/j.ajhg.2013.05.024
26. Renauer PA, Saruhan-Direskeneli G, Coit P, Adler A, Aksu K, Keser G, et al. Identification of susceptibility loci in IL6, RPS9/LILRB3, and an intergenic locus on chromosome 21q22 in Takayasu arteritis in a genome-wide association study. Arthritis Rheumatol (2015) 67(5):1361–8. doi:10.1002/art.39035
27. Fei Y, Webb R, Cobb BL, Direskeneli H, Saruhan-Direskeneli G, Sawalha AH. Identification of novel genetic susceptibility loci for Behcet’s disease using a genome-wide association study. Arthritis Res Ther (2009) 11(3):R66. doi:10.1186/ar2695
28. Hou S, Yang Z, Du L, Jiang Z, Shu Q, Chen Y, et al. Identification of a susceptibility locus in STAT4 for Behcet’s disease in Han Chinese in a genome-wide association study. Arthritis Rheum (2012) 64(12):4104–13. doi:10.1002/art.37708
29. Kappen JH, Medina-Gomez C, van Hagen PM, Stolk L, Estrada K, Rivadeneira F, et al. Genome-wide association study in an admixed case series reveals IL12A as a new candidate in Behcet disease. PLoS One (2015) 10(3):e0119085. doi:10.1371/journal.pone.0119085
31. Kirino Y, Bertsias G, Ishigatsubo Y, Mizuki N, Tugal-Tutkun I, Seyahi E, et al. Genome-wide association analysis identifies new susceptibility loci for Behcet’s disease and epistasis between HLA-B*51 and ERAP1. Nat Genet (2013) 45(2):202–7. doi:10.1038/ng.2520
32. Lee YJ, Horie Y, Wallace GR, Choi YS, Park JA, Choi JY, et al. Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behcet’s disease. Ann Rheum Dis (2013) 72(9):1510–6. doi:10.1136/annrheumdis-2011-200288
33. Mizuki N, Meguro A, Ota M, Ohno S, Shiota T, Kawagoe T, et al. Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behcet’s disease susceptibility loci. Nat Genet (2010) 42(8):703–6. doi:10.1038/ng.624
34. Remmers EF, Cosan F, Kirino Y, Ombrello MJ, Abaci N, Satorius C, et al. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet’s disease. Nat Genet (2010) 42(8):698–702. doi:10.1038/ng.625
35. Xavier JM, Shahram F, Sousa I, Davatchi F, Matos M, Abdollahi BS, et al. FUT2: filling the gap between genes and environment in Behcet’s disease? Ann Rheum Dis (2015) 74(3):618–24. doi:10.1136/annrheumdis-2013-204475
38. Bakir-Gungor B, Remmers EF, Meguro A, Mizuki N, Kastner DL, Gul A, et al. Identification of possible pathogenic pathways in Behcet’s disease using genome-wide association study data from two different populations. Eur J Hum Genet (2015) 23(5):678–87. doi:10.1038/ejhg.2014.158
40. Navon Elkan P, Pierce SB, Segel R, Walsh T, Barash J, Padeh S, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med (2014) 370(10):921–31. doi:10.1056/NEJMoa1307362
41. Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med (2014) 370(10):911–20. doi:10.1056/NEJMoa1307361
42. Garg N, Kasapcopur O, Foster J II, Barut K, Tekin A, Kizilkilic O, et al. Novel adenosine deaminase 2 mutations in a child with a fatal vasculopathy. Eur J Pediatr (2014) 173(6):827–30. doi:10.1007/s00431-014-2320-8
44. Batu ED, Karadag O, Taskiran EZ, Kalyoncu U, Aksentijevich I, Alikasifoglu M, et al. A case series of adenosine deaminase 2-deficient patients emphasizing treatment and genotype-phenotype correlations. J Rheumatol (2015) 42(8):1532–4. doi:10.3899/jrheum.150024
46. Hashem H, Kumar AR, Muller I, Babor F, Bredius R, Dalal J, et al. Hematopoietic stem cell transplantation rescues the hematological, immunological, and vascular phenotype in DADA2. Blood (2017) 130(24):2682–8. doi:10.1182/blood-2017-07-798660
49. Munoz J, Rodiere M, Jeremiah N, Rieux-Laucat F, Oojageer A, Rice GI, et al. Stimulator of interferon genes-associated vasculopathy with onset in infancy: a mimic of childhood granulomatosis with polyangiitis. JAMA Dermatol (2015) 151(8):872–7. doi:10.1001/jamadermatol.2015.0251
50. Sanchez GAM, Reinhardt A, Ramsey S, Wittkowski H, Hashkes PJ, Berkun Y, et al. JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest (2018) 128(7):3041–52. doi:10.1172/JCI98814
51. Zhou Q, Wang H, Schwartz DM, Stoffels M, Park YH, Zhang Y, et al. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat Genet (2016) 48(1):67–73. doi:10.1038/ng.3459
52. Aeschlimann FA, Batu ED, Canna SW, Go E, Gul A, Hoffmann P, et al. A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease. Ann Rheum Dis (2018) 77(5):728–35. doi:10.1136/annrheumdis-2017-212403
53. Berteau F, Rouviere B, Nau A, Le Berre R, Sarrabay G, Touitou I, et al. Response to: ’A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease’. Ann Rheum Dis (2018). doi:10.1136/annrheumdis-2018-213347
54. Duncan CJA, Dinnigan E, Theobald R, Grainger A, Skelton AJ, Hussain R, et al. Early-onset autoimmune disease due to a heterozygous loss-of-function mutation in TNFAIP3 (A20). Ann Rheum Dis (2018) 77(5):783–6. doi:10.1136/annrheumdis-2016-210944
55. Franco-Jarava C, Wang H, Martin-Nalda A, Alvarez SD, Garcia-Prat M, Bodet D, et al. TNFAIP3 haploinsufficiency is the cause of autoinflammatory manifestations in a patient with a deletion of 13Mb on chromosome 6. Clin Immunol (2018) 191:44–51. doi:10.1016/j.clim.2018.03.009
56. Kadowaki T, Ohnishi H, Kawamoto N, Hori T, Nishimura K, Kobayashi C, et al. Haploinsufficiency of A20 causes autoinflammatory and autoimmune disorders. J Allergy Clin Immunol (2018) 141(4):1485–8.e11. doi:10.1016/j.jaci.2017.10.039
57. Ohnishi H, Kawamoto N, Seishima M, Ohara O, Fukao T. A Japanese family case with juvenile onset Behcet’s disease caused by TNFAIP3 mutation. Allergol Int (2017) 66(1):146–8. doi:10.1016/j.alit.2016.06.006
58. Shigemura T, Kaneko N, Kobayashi N, Kobayashi K, Takeuchi Y, Nakano N, et al. Novel heterozygous C243Y A20/TNFAIP3 gene mutation is responsible for chronic inflammation in autosomal-dominant Behcet’s disease. RMD Open (2016) 2(1):e000223. doi:10.1136/rmdopen-2015-000223
59. Takagi M, Ogata S, Ueno H, Yoshida K, Yeh T, Hoshino A, et al. Haploinsufficiency of TNFAIP3 (A20) by germline mutation is involved in autoimmune lymphoproliferative syndrome. J Allergy Clin Immunol (2017) 139(6):1914–22. doi:10.1016/j.jaci.2016.09.038
60. Viel S, Cheyssac E, Pescarmona R, Besson L, Till M, Viremouneix L, et al. Large deletion in 6q associated to A20 haploinsufficiency and thoracoabdominal heterotaxy. Ann Rheum Dis (2018). doi:10.1136/annrheumdis-2018-213300
61. Ye Z, Zhou Y, Huang Y, Wang Y, Lu J, Tang Z, et al. Phenotype and management of infantile-onset inflammatory bowel disease: experience from a tertiary care center in China. Inflamm Bowel Dis (2017) 23(12):2154–64. doi:10.1097/MIB.0000000000001269
63. Tunca M, Akar S, Onen F, Ozdogan H, Kasapcopur O, Yalcinkaya F, et al. Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (2005) 84(1):1–11. doi:10.1097/01.md.0000152370.84628.0c
64. Jain A, Misra DP, Sharma A, Wakhlu A, Agarwal V, Negi VS. Vasculitis and vasculitis-like manifestations in monogenic autoinflammatory syndromes. Rheumatol Int (2018) 38(1):13–24. doi:10.1007/s00296-017-3839-6
67. Schwartz T, Langevitz P, Zemer D, Gazit E, Pras M, Livneh A. Behcet’s disease in Familial Mediterranean fever: characterization of the association between the two diseases. Semin Arthritis Rheum (2000) 29(5):286–95. doi:10.1016/S0049-0172(00)80015-3
68. Touitou I, Magne X, Molinari N, Navarro A, Quellec AL, Picco P, et al. MEFV mutations in Behcet’s disease. Hum Mutat (2000) 16(3):271–2. doi:10.1002/1098-1004(200009)16:3<271:AID-HUMU16>3.0.CO;2-A
69. Wu Z, Zhang S, Li J, Chen S, Li P, Sun F, et al. Association between MEFV mutations M694V and M680I and Behcet’s disease: a meta-analysis. PLoS One (2015) 10(7):e0132704. doi:10.1371/journal.pone.0132704
71. Sun L, Xie B, Zhang Q, Wang Y, Wang X, Gao B, et al. Biomarkers identification by a combined clinical and metabonomics analysis in Henoch-Schonlein purpura nephritis children. Oncotarget (2017) 8(69):114239–50. doi:10.18632/oncotarget.23207
72. Berthelot L, Jamin A, Viglietti D, Chemouny JM, Ayari H, Pierre M, et al. Value of biomarkers for predicting immunoglobulin A vasculitis nephritis outcome in an adult prospective cohort. Nephrol Dial Transplant (2017) gfx300. doi:10.1093/ndt/gfx300
73. Ge W, Wang HL, Sun RP. Pentraxin 3 as a novel early biomarker for the prediction of Henoch-Schonlein purpura nephritis in children. Eur J Pediatr (2014) 173(2):213–8. doi:10.1007/s00431-013-2150-0
75. Zhang L, Han C, Sun C, Meng H, Ye F, Na S, et al. Serum levels of alpha-smooth muscle actin and c-Met as biomarkers of the degree of severity of Henoch-Schonlein purpura nephritis. Transl Res (2013) 161(1):26–36. doi:10.1016/j.trsl.2012.09.001
76. Zhou TB, Yin SS. Association of matrix metalloproteinase-9 level with the risk of renal involvement for Henoch-Schonlein purpura in children. Ren Fail (2013) 35(3):425–9. doi:10.3109/0886022X.2012.757826
77. Jiang J, Duan W, Shang X, Wang H, Gao Y, Tian P, et al. Inducible nitric oxide synthase gene polymorphisms are associated with a risk of nephritis in Henoch-Schonlein purpura children. Eur J Pediatr (2017) 176(8):1035–45. doi:10.1007/s00431-017-2945-5
78. Lopez-Mejias R, Genre F, Remuzgo-Martinez S, Sevilla Perez B, Castaneda S, Llorca J, et al. Interleukin 1 beta (IL1ss) rs16944 genetic variant as a genetic marker of severe renal manifestations and renal sequelae in Henoch-Schonlein purpura. Clin Exp Rheumatol (2016) 34(3 Suppl 97):S84–8.
79. Gunasekaran TS, Berman J, Gonzalez M. Duodenojejunitis: is it idiopathic or is it Henoch-Schonlein purpura without the purpura? J Pediatr Gastroenterol Nutr (2000) 30(1):22–8. doi:10.1097/00005176-200001000-00013
80. Kawasaki K, Komura H, Nakahara Y, Shiraishi M, Higashida M, Ouchi K. Factor XIII in Henoch-Schonlein purpura with isolated gastrointestinal symptoms. Pediatr Int (2006) 48(4):413–5. doi:10.1111/j.1442-200X.2006.02232.x
81. Guo MM, Tseng WN, Ko CH, Pan HM, Hsieh KS, Kuo HC. Th17- and Treg-related cytokine and mRNA expression are associated with acute and resolving Kawasaki disease. Allergy (2015) 70(3):310–8. doi:10.1111/all.12558
82. Yamamoto N, Sato K, Hoshina T, Kojiro M, Kusuhara K. Utility of ferritin as a predictor of the patients with Kawasaki disease refractory to intravenous immunoglobulin therapy. Mod Rheumatol (2015) 25(6):898–902. doi:10.3109/14397595.2015.1038430
83. Okuma Y, Suda K, Nakaoka H, Katsube Y, Mitani Y, Yoshikane Y, et al. Serum tenascin-C as a novel predictor for risk of coronary artery lesion and resistance to intravenous immunoglobulin in Kawasaki disease – a multicenter retrospective study. Circ J (2016) 80(11):2376–81. doi:10.1253/circj.CJ-16-0563
84. Sato S, Kawashima H, Kashiwagi Y, Hoshika A. Inflammatory cytokines as predictors of resistance to intravenous immunoglobulin therapy in Kawasaki disease patients. Int J Rheum Dis (2013) 16(2):168–72. doi:10.1111/1756-185X.12082
85. Motoki N, Akazawa Y, Yamazaki S, Hachiya A, Motoki H, Matsuzaki S, et al. Prognostic significance of QT interval dispersion in the response to intravenous immunoglobulin therapy in Kawasaki disease. Circ J (2017) 81(4):537–42. doi:10.1253/circj.CJ-16-0864
86. Ye Q, Gong FQ, Shang SQ, Hu J. Intravenous immunoglobulin treatment responsiveness depends on the degree of CD8+ T cell activation in Kawasaki disease. Clin Immunol (2016) 171:25–31. doi:10.1016/j.clim.2016.08.012
87. Kirchhof MG, Lee AY, Dutz JP. D-dimer levels as a marker of cutaneous disease activity: case reports of cutaneous polyarteritis nodosa and atypical recurrent urticaria. JAMA Dermatol (2014) 150(8):880–4. doi:10.1001/jamadermatol.2013.9944
88. Navarro M, Cervera R, Font J, Reverter JC, Monteagudo J, Escolar G, et al. Anti-endothelial cell antibodies in systemic autoimmune diseases: prevalence and clinical significance. Lupus (1997) 6(6):521–6. doi:10.1177/096120339700600608
89. Okano T, Takeuchi S, Soma Y, Suzuki K, Tsukita S, Ishizu A, et al. Presence of anti-phosphatidylserine-prothrombin complex antibodies and anti-moesin antibodies in patients with polyarteritis nodosa. J Dermatol (2017) 44(1):18–22. doi:10.1111/1346-8138.13491
90. Fussner LA, Hummel AM, Schroeder DR, Silva F, Cartin-Ceba R, Snyder MR, et al. Factors determining the clinical utility of serial measurements of antineutrophil cytoplasmic antibodies targeting proteinase 3. Arthritis Rheumatol (2016) 68(7):1700–10. doi:10.1002/art.39637
91. Kemna MJ, Damoiseaux J, Austen J, Winkens B, Peters J, van Paassen P, et al. ANCA as a predictor of relapse: useful in patients with renal involvement but not in patients with nonrenal disease. J Am Soc Nephrol (2015) 26(3):537–42. doi:10.1681/ASN.2013111233
92. Lionaki S, Blyth ER, Hogan SL, Hu Y, Senior BA, Jennette CE, et al. Classification of antineutrophil cytoplasmic autoantibody vasculitides: the role of antineutrophil cytoplasmic autoantibody specificity for myeloperoxidase or proteinase 3 in disease recognition and prognosis. Arthritis Rheum (2012) 64(10):3452–62. doi:10.1002/art.34562
93. Murosaki T, Sato T, Akiyama Y, Nagatani K, Minota S. Difference in relapse-rate and clinical phenotype by autoantibody-subtype in Japanese patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Mod Rheumatol (2017) 27(1):95–101. doi:10.1080/14397595.2016.1192760
94. Schirmer JH, Wright MN, Herrmann K, Laudien M, Nolle B, Reinhold-Keller E, et al. Myeloperoxidase-antineutrophil cytoplasmic antibody (ANCA)-positive granulomatosis with polyangiitis (Wegener’s) is a clinically distinct subset of ANCA-associated vasculitis: a retrospective analysis of 315 patients from a German vasculitis referral center. Arthritis Rheumatol (2016) 68(12):2953–63. doi:10.1002/art.39786
95. Kemna MJ, Plomp R, van Paassen P, Koeleman CAM, Jansen BC, Damoiseaux J, et al. Galactosylation and sialylation levels of IgG predict relapse in patients with PR3-ANCA associated vasculitis. EBioMedicine (2017) 17:108–18. doi:10.1016/j.ebiom.2017.01.033
96. Ishizaki J, Takemori A, Suemori K, Matsumoto T, Akita Y, Sada KE, et al. Targeted proteomics reveals promising biomarkers of disease activity and organ involvement in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Res Ther (2017) 19(1):218. doi:10.1186/s13075-017-1429-3
97. Rani L, Minz RW, Arora A, Kannan M, Sharma A, Anand S, et al. Serum proteomic profiling in granumomatosis with polyangiitis using two-dimensional gel electrophoresis along with matrix assisted laser desorption ionization time of flight mass spectrometry. Int J Rheum Dis (2014) 17(8):910–9. doi:10.1111/1756-185X.12481
98. Stone JH, Rajapakse VN, Hoffman GS, Specks U, Merkel PA, Spiera RF, et al. A serum proteomic approach to gauging the state of remission in Wegener’s granulomatosis. Arthritis Rheum (2005) 52(3):902–10. doi:10.1002/art.20938
99. McKinney EF, Lyons PA, Carr EJ, Hollis JL, Jayne DR, Willcocks LC, et al. A CD8+ T cell transcription signature predicts prognosis in autoimmune disease. Nat Med (2010) 16(5):586–91, 1p following 91. doi:10.1038/nm.2130
101. Unizony S, Villarreal M, Miloslavsky EM, Lu N, Merkel PA, Spiera R, et al. Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type. Ann Rheum Dis (2016) 75(6):1166–9. doi:10.1136/annrheumdis-2015-208073
102. Haubitz M, Good DM, Woywodt A, Haller H, Rupprecht H, Theodorescu D, et al. Identification and validation of urinary biomarkers for differential diagnosis and evaluation of therapeutic intervention in anti-neutrophil cytoplasmic antibody-associated vasculitis. Mol Cell Proteomics (2009) 8(10):2296–307. doi:10.1074/mcp.M800529-MCP200
103. Hong Y, Eleftheriou D, Hussain AA, Price-Kuehne FE, Savage CO, Jayne D, et al. Anti-neutrophil cytoplasmic antibodies stimulate release of neutrophil microparticles. J Am Soc Nephrol (2012) 23(1):49–62. doi:10.1681/ASN.2011030298
106. Wang H, Sha LL, Ma TT, Zhang LX, Chen M, Zhao MH. Circulating level of neutrophil extracellular traps is not a useful biomarker for assessing disease activity in antineutrophil cytoplasmic antibody-associated vasculitis. PLoS One (2016) 11(2):e0148197. doi:10.1371/journal.pone.0148197
107. Deshayes S, Aouba A, Khoy K, Mariotte D, Lobbedez T, Martin Silva N. Hypocomplementemia is associated with worse renal survival in ANCA-positive granulomatosis with polyangiitis and microscopic polyangiitis. PLoS One (2018) 13(4):e0195680. doi:10.1371/journal.pone.0195680
108. Jayne DRW, Bruchfeld AN, Harper L, Schaier M, Venning MC, Hamilton P, et al. Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitis. J Am Soc Nephrol (2017) 28(9):2756–67. doi:10.1681/ASN.2016111179
109. Becker H, Maaser C, Mickholz E, Dyong A, Domschke W, Gaubitz M. Relationship between serum levels of macrophage migration inhibitory factor and the activity of antineutrophil cytoplasmic antibody-associated vasculitides. Clin Rheumatol (2006) 25(3):368–72. doi:10.1007/s10067-005-0045-9
110. Kim HJ, Jung SM, Song JJ, Park YB, Lee SW. Mean platelet volume can estimate the current vasculitis activity of microscopic polyangiitis. Rheumatol Int (2018) 38(6):1095–101. doi:10.1007/s00296-018-4011-7
111. Kucuk H, Varan O, Goker B, Bitik B, Ozturk MA, Haznedaroglu S, et al. Serum ferritin as an activity marker for granulamotosis with polyangiitis. Ren Fail (2017) 39(1):566–9. doi:10.1080/0886022X.2017.1349675
112. Watanabe S, Gono T, Nishina K, Sugitani N, Watanabe E, Yabe H, et al. Rheumatoid factor is correlated with disease activity and inflammatory markers in antineutrophil cytoplasmic antibody-associated vasculitis. BMC Immunol (2017) 18(1):53. doi:10.1186/s12865-017-0234-8
113. Yoo J, Ahn SS, Jung SM, Song JJ, Park YB, Lee SW. Delta neutrophil index is associated with vasculitis activity and risk of relapse in ANCA-associated vasculitis. Yonsei Med J (2018) 59(3):397–405. doi:10.3349/ymj.2018.59.3.397
114. Dagna L, Salvo F, Tiraboschi M, Bozzolo EP, Franchini S, Doglioni C, et al. Pentraxin-3 as a marker of disease activity in Takayasu arteritis. Ann Intern Med (2011) 155(7):425–33. doi:10.7326/0003-4819-155-7-201110040-00005
115. Matsuyama A, Sakai N, Ishigami M, Hiraoka H, Kashine S, Hirata A, et al. Matrix metalloproteinases as novel disease markers in Takayasu arteritis. Circulation (2003) 108(12):1469–73. doi:10.1161/01.CIR.0000090689.69973.B1
116. Noguchi S, Numano F, Gravanis MB, Wilcox JN. Increased levels of soluble forms of adhesion molecules in Takayasu arteritis. Int J Cardiol (1998) 66(Suppl 1):S23–33. doi:10.1016/S0167-5273(98)00145-4
119. Mahajan N, Dhawan V, Mahmood S, Malik S, Jain S. Extracellular matrix remodeling in Takayasu’s arteritis: role of matrix metalloproteinases and adventitial inflammation. Arch Med Res (2012) 43(5):406–10. doi:10.1016/j.arcmed.2012.07.007
120. Sun Y, Ma L, Yan F, Liu H, Ding Y, Hou J, et al. MMP-9 and IL-6 are potential biomarkers for disease activity in Takayasu’s arteritis. Int J Cardiol (2012) 156(2):236–8. doi:10.1016/j.ijcard.2012.01.035
121. Tamura N, Maejima Y, Tezuka D, Takamura C, Yoshikawa S, Ashikaga T, et al. Profiles of serum cytokine levels in Takayasu arteritis patients: potential utility as biomarkers for monitoring disease activity. J Cardiol (2017) 70(3):278–85. doi:10.1016/j.jjcc.2016.10.016
123. Batu ED, Sonmez HE, Hazirolan T, Ozaltin F, Bilginer Y, Ozen S. Tocilizumab treatment in childhood Takayasu arteritis: case series of four patients and systematic review of the literature. Semin Arthritis Rheum (2017) 46(4):529–35. doi:10.1016/j.semarthrit.2016.07.012
124. Comarmond C, Plaisier E, Dahan K, Mirault T, Emmerich J, Amoura Z, et al. Anti TNF-alpha in refractory Takayasu’s arteritis: cases series and review of the literature. Autoimmun Rev (2012) 11(9):678–84. doi:10.1016/j.autrev.2011.11.025
125. Goel R, Nair A, Kabeerdoss J, Mohan H, Jeyaseelan V, Joseph G, et al. Study of serial serum myeloid-related protein 8/14 as a sensitive biomarker in Takayasu arteritis: a single centre study. Rheumatol Int (2018) 38(4):623–30. doi:10.1007/s00296-017-3881-4
126. Goel R, Kabeerdoss J, Mohan H, Danda S, Jayaseelan V, Kumar TS, et al. Soluble-HLA-E: a follow up biomarker in Takayasu arteritis, independent of HLA-E genotype. Int J Rheum Dis (2018) 21(2):532–40. doi:10.1111/1756-185X.13027
129. Tulunay A, Dozmorov MG, Ture-Ozdemir F, Yilmaz V, Eksioglu-Demiralp E, Alibaz-Oner F, et al. Activation of the JAK/STAT pathway in Behcet’s disease. Genes Immun (2015) 16(2):170–5. doi:10.1038/gene.2014.64
131. Akman-Demir G, Tuzun E, Icoz S, Yesilot N, Yentur SP, Kurtuncu M, et al. Interleukin-6 in neuro-Behcet’s disease: association with disease subsets and long-term outcome. Cytokine (2008) 44(3):373–6. doi:10.1016/j.cyto.2008.10.007
132. Borhani Haghighi A, Ittehadi H, Nikseresht AR, Rahmati J, Poorjahromi SG, Pourabbas B, et al. CSF levels of cytokines in neuro-Behcet’s disease. Clin Neurol Neurosurg (2009) 111(6):507–10. doi:10.1016/j.clineuro.2009.02.001
133. Gholijani N, Ataollahi MR, Samiei A, Aflaki E, Shenavandeh S, Kamali-Sarvestani E. An elevated pro-inflammatory cytokines profile in Behcet’s disease: a multiplex analysis. Immunol Lett (2017) 186:46–51. doi:10.1016/j.imlet.2016.12.001
135. Lopalco G, Lucherini OM, Lopalco A, Venerito V, Fabiani C, Frediani B, et al. Cytokine signatures in mucocutaneous and ocular Behcet’s disease. Front Immunol (2017) 8:200. doi:10.3389/fimmu.2017.00200
137. Pay S, Erdem H, Pekel A, Simsek I, Musabak U, Sengul A, et al. Synovial proinflammatory cytokines and their correlation with matrix metalloproteinase-3 expression in Behcet’s disease. Does interleukin-1beta play a major role in Behcet’s synovitis? Rheumatol Int (2006) 26(7):608–13. doi:10.1007/s00296-005-0040-0
Keywords: systemic vasculitis, genome-wide association studies, monogenic vasculitis, biomarker, precision medicine
Citation: Ozen S and Batu ED (2018) Vasculitis Pathogenesis: Can We Talk About Precision Medicine? Front. Immunol. 9:1892. doi: 10.3389/fimmu.2018.01892
Received: 14 May 2018; Accepted: 31 July 2018;
Published: 14 August 2018
Edited by:Alexandre Belot, Hospices Civils de Lyon, France
Reviewed by:Sophie Anne Georgin-Lavialle, Université Pierre et Marie Curie, France
Sinisa Savic, University of Leeds, United Kingdom
Copyright: © 2018 Ozen and Batu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.