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Oral aphthous ulcers are recurrent mucosal ulcers producing significant discomfort and pain for the patient and also the most frequent finding in BD. They tend to reoccur frequently and as much as every days or every month. These ulcers can last for days and when they heal, it is usually without much scarring except for ulcers that are large. Skin lesions in BD have many presentations. These include erythema nodosum, which are painful, purple-colored, nodules that present over the extensor surfaces of the lower extremities, especially the tibias, but can also occur on the face, neck, and buttocks.

Although somewhat unique, pathergy is not pathognomonic of BD. Genital ulcers grossly resemble oral aphthous ulcers. They can occur on the scrotum or penis in males or on the vulva and the vaginal mucosa in females. They can also appear on the anus in both sexes.

The genital ulcers in BD are associated with variable amounts of pain. Healing takes longer than oral ulcers, generally up to 3 weeks, and unlike the oral ulcers they often scar. As with the retina, systemically both arteries and veins of any size may be affected. Arterial occlusion, aneurysm, venous occlusion, and varices are four of the common complications of the systemic vasculitis in BD.

Areas of motor control are mainly affected with neurologic involvement. Ocular signs and symptoms of neuro-BD include cranial nerve palsies, papillitis causing central scotoma, visual field defects, and superior sagittal sinus or other venous sinuses thrombosis causing papilledema. Although rare, renal involvement in BD is characterized as a nephrotic syndrome. Other manifestations of active BD that can also be present include amyloidosis, myositis, and epididymitis.

There are reports of familial clustering, but it is actually rare to see other family members affected with BD, even when many family members have the HLA-B51 gene. This fact makes the presence of HLA-B51 alone a minor factor. Given that BD is of unknown etiology, the highest prevalence of the disease is found in the Middle East and Far East, particularly Japan. Since the same clinical manifestations are found across different ethnic groups, it is presumed that environmental factors likely also play a role along with genetic predisposition. There are many postulated genetic and environmental factors that are presumed to play a role.

Abnormal immune activity may be generated by exposure to infectious viral and bacterial or non-infectious environmental sources, such as heavy metals or chemicals antigens in patients with a genetic predisposition. Lesions within the eye may show blood vessel infiltration by leukocytes, retinal vasculitis with occlusions, and thrombosis.

The anterior chamber, as well as the corneal epithelium, iris, ciliary body, and choroids may show neutrophil infiltration during active disease [18]. No studies have been effective at producing definitive information regarding the primary prevention, given the etiology of BD is unknown. Diagnosis of BD is based on clinical findings and the diagnostic criteria listed below.

Many different tests can help aid towards inclusion or exclusion of BD, including HLA Testing and cutaneous pathergy testing. The nonspecific serologic markers of inflammation i. ESR and C-reactive protein usually provide little value in confirming the diagnosis. Fluorescein angiography performed on ocular BD patients may demonstrate marked dilatation and occlusion of retinal capillaries with perivascular staining.

On angiography, there can also be evidence of retinal non-perfusion hypofluorescence and neovascularization areas of intense, early hyperfluorescence along vascular distributions. There may also be petalloid macular leakage of fluorescein if CME is present. Based on the clinical presentation of a BD patient, certain radiologic imaging tests including chest x-ray, chest CT, and brain MRI with contrast enhancement, can be helpful. Anterior uveitis presents with painful eyes, conjunctival redness, hypopyon, photophobia, tearing, blurry vision, and decreased visual acuity.

Posterior uveitis may be more dangerous and vision—threatening because it often causes fewer symptoms while damaging the retina. Symptoms include painless decreased visual acuity and floaters. Retinal vasculitis may present with a painless decrease of vision. Patients may note floaters or visual field defects.

Retinal vasculitis manifests as retinal hemorrhages and retinal capillary hypoperfusion on fluorescein angiogram. Optic nerve atrophy is the most common cause of visual impairment. There are both primary and secondary causes of optic nerve involvement. Secondary causes of optic nerve atrophy include papilledema from dural sinus thrombosis [20] and atrophy from retinal disease.

Signs and symptoms of acute optic neuropathy include painless loss of vision which may affect either one or both eyes, reduced visual acuity, reduced color vision, relative afferent pupullary defect APD , central scotoma, swollen optic disc, macular edema or retrobulbar pain. Progressive optic atrophy may result in decreased visual acuity or color vision. Aphthous ulcers affect almost all patients with Behcet's disease. Individual sores or ulcers are usually identical to canker sores, which are common in many people.

These sores are usually a result of minor trauma. They are often the first symptom that a person notices and may occur long before any other symptoms appear. However, the lesions are more numerous, more frequent, and often larger and more painful. Skin problems are a common symptom of Behcet's disease. Skin sores often look red or resemble pus-filled bumps or a bruise.

The sores are red and raised, and typically appear on the legs and on the upper torso. Pustular skin lesions that resemble acne, but can occur nearly anywhere on the body. Erythema nodosum: red, tender nodules that usually occur on the legs and ankles but also appear sometimes on the face, neck, or arms. Central nervous system involvement in BD included parenchymal and non-parenchymal i.

They include headache, meningitis or meningoencephalitis, seizures, hemiplegia, or cranial nerve palsies. The benign intracranial hypertension is always related, in our experience of 64 cases, to cerebral venous thrombosis [ 20 ]. Psychiatric symptoms including personality changes may develop.

In some cases it may be difficult to differentiate the organic manifestations from the iatrogenic side effects of therapy. Lumbar puncture with measurement of the open pressure is mandatory. It usually shows hypercellularity; mostly lymphocytosis and less frequently polymorphonuclear cells or pleiocytosis. Cerebrospinal fluid analysis rule out an infection such as tuberculosis, listeriosis or herpes simplex virus. Typical MRI findings are small scattered lesions in multiple area of basal ganglion region, brainstem or internal capsule, with hypersignal in T2-weighted MRI and contrast enhancement with Gadolinium.

They may attenuate with therapy but a retrospective diagnosis is generally feasible. Prognosis is severe but improvement is observed with intensive and rapid therapy including corticosteroids and immunosuppressive drugs. It is difficult to distinguish between BD and inflammatory diseases of the intestine, because of the similarity in intestinal and extra intestinal symptoms.

Gastrointestinal involvement causes nausea, abdominal pain, anorexia, diarrhea which can be bloody and sometimes can lead to perforation. The ileocecal region is the most commonly affected part of the gastrointestinal tract, but tranverse colon and ascending colon are sometimes involved, as is the esophagus. Histologically, the intestinal ulcers are indistinguishable from Crohn's disease, nevertheless the granuloma formation can be used to rule out BD. Cases of acute pancreatitis have been reported.

It is dominated by vascular involvement arterial aneurysm, pulmonary embolism. Hemoptysis can be massive and fatal and is the main manifestation [ 14 ]. Pleural effusions are rare and lead to firstly rule out pulmonary embolism, tuberculosis or nosocomial infection. Cases of vasculitis have been reported.

Renal involvement is rare and dominated by AA amyloidosis occuring in patients with long standing disease not controlled with therapy or not compliant. Some cases of glomerular nephropathy mostly diffuse crescentic or focal and segmental necrotizing glomerulonephritis and IgA nephropathy have been described. Secondary effects of venous or arterial thrombosis have also been reported. Lymph or splenic enlargement may exceptionally be the presenting feature and should be thoroughly evaluated.

When fever is present, vascular involvement has to be searched for. The implication of T cells and polymorphonuclear leukocytes is supported by pathological studies showing perivascular infiltration of memory T cells and polymorphonuclear leucocytes within vasculitic lesions in BD patients with arterial and central nervous system CNS involvement [ 26 , 27 ]. However, the nature of T cells driving inflammatory lesions remains elusive. We recently demonstrated the promotion of Th17 responses and the suppression of regulatory T cells Tregs that were induced by interleukin IL production and that correlates with BD activity [ 28 ].

Our findings suggest that IL exerts a critical role in the pathogenesis of BD, thus providing a promising target for novel therapy [ 28 ]. In BD there is no relevant biological test for diagnosis. Abnormalities of fibrinolysis, elevated factor VIII, immune circulating complexes and cryoglobulinemia have been occasionally reported.

Leucocytosis is frequently encountered. The positivity of HLA B 51 allele is of no diagnostic value. Cutaneous biopsy of intradermal injection with physiologic saline solution may demonstrate vasculitis with immune complexes deposit. The diagnosis of BD is only supported by clinical criteria that require the exclusion of other diagnoses based on clinical presentation. In contrast, bipolar ulcerations are more specific of BD. Venous involvement should exclude the antiphospholipid syndrome, or thrombophilia.

Neuro-BD is sometimes difficult to distinguish from multiple sclerosis or tuberculosis. Lastly, chronic inflammatory bowel disorders must be ruled out in case of gastrointestinal involvement. Due to the lack of an etiologic agent, the treatment is symptomatic without consensus. EULAR recommendations for the management of BD, based on the available literature and expert opinions, have been recently proposed [ 29 ].

The goals are the functional recovery of a visceral involvement eye, CNS and prevention of relapse s. The risks of BD are an increased mortality especially in case of arterial involvement, and a high morbidity due to the cumulative sequellae of ocular and neurological involvement [ 7 , 30 ]. Steroids are the corner stone of the antiinflammatory agents administered topically anterior uveitis or systemically. Initiation of therapy could be made by infusion of methylprednisolone 1 g. When steroids are used, they can be reduced with caution after 4 weeks.

Relapses are frequently seen after discontinuation of steroids. Corticodependance is frequently observed. Immunosuppressive drugs have been shown to be effective. Due to their delay of action, they are prescribed initially in association with corticosteroids. They are prescribed in cases of severe organ involvement i.

Azathioprine 2. The efficacy of oral methotrexate 7.

Chloraminophen 0. Ciclosporin was proved effective in uveitis [ 29 ], but secondary nephropathy limits its prescription. More recently the efficacy of infliximab has been reported in severe cases of BD uveitis [ 32 ]. Plasmapheresis and intravenous immunoglobulins were efficient in anecdotal reports.


We used it systematically in adjunction with other therapeutic agents. Severe flares of BD were observed after cessation of this drug. Thalidomide is also reported to be effective for oral and genital ulcers and pseudofolliculitis with relapses when stopped [ 35 ]. Among side effects, peripheral neuropathy is frequent. Disulone, Sucralfate, and Pentoxifylline have shown some efficacy in anecdotal reports [ 36 , 37 ].

As for other chronic diseases, patient education, good compliance, regular follow-up and rapid therapeutic administration improve the prognosis. BD significantly increases morbidity and mortality. The leading causes of morbidity in BD are the uveitis with the potential threat of visual loss and neurologic involvement.

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 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. 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.

Deficiency of adenosine deaminase 2 is associated with CECR1 mutations and causes a PAN-like vasculopathy and autoinflammatory features ADA2 is thought to trigger the macrophages to have an inflammatory phenotype and endothelial integrity is compromised in DADA2 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 — DADA2 patients may also present with only hematological features such as pure red cell anemia 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 , Hematopoietic stem cell transplantation should be especially considered in DADA2 patients with bone marrow failure who display predominant hematological features Recently, Sanchez et al. Around 50 HA20 patients have been reported so far with early-onset recurrent mucosal ulcers resembling BD being the hallmark feature in most 51 — 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 Familial Mediterranean fever is the most common autoinflammatory disease characterized by fever and polyserositis attacks and caused by MEFV mutations The mutations in this gene are associated with increased IL-1 production.

Qualitative study: the experience and impact of living with Behcet’s syndrome

Colchicine is the mainstay of FMF treatment Certain vasculitides are more frequent in FMF patients than normal population 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 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 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.

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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.

Table 2. The main biomarkers that serve targets for treatment in primary systemic vasculitides. A few studies are present on biomarkers of prognosis for gastrointestinal involvement, as well. Sun et al. Berthelot et al. Thus, these biomarkers may guide us in how we manage these patients in the coming days. Administration of factor XIII concentrate lead to improvement of gastrointestinal complaints in anecdotal case reports Early use of biologics may also be indicated in selected cases.

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 — However, none of these are currently being used in routine medical practice in the management of patients with PAN.

These are mainly diagnostic biomarkers and their use for monitoring disease activity is controversial.

Immune Regulatory Genes Are Major Genetic Factors to Behcet Disease: Systematic Review

In the recent targeted proteomics study, Ishizaki et al. 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 , McKinney et al. 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 As to biomarkers for response to treatment in AAV, Unizony et al.

Haubitz et al. Hong et al. In the same lines, endothelial MPs, important biomarkers of endothelial injury, may be important targets to be removed by plasma exchange in AAV Neutrophil extracellular traps, composed of DNA, histones, and neutrophil proteins, are released by neutrophils under the influence of inflammatory stimuli Kessenbrock et al. Recent studies have highlighted the role of complement alternative pathway activation in AAV pathogenesis In a recent randomized trial, Jayne et al. 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 — 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. Goel et al. As genetic factors, a recently studied biomarker in TA, is human leukocyte antigen E HLA-Bw52 was previously shown to be associated with higher incidence of cardiovascular events and poorer prognosis in TA patients Terao et al. 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.

However, several of these biomarkers may be targeted in BD treatment.

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Sadeghi et al. The authors have thus concluded that IL-2 may be a new target for treatment of refractory BD uveitis. Tulunay et al. 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. SO is receiving consultancy fees from Novartis and Eczacibasi. EB declares no conflict of interest. The Definition of Precision Medicine. Google Scholar. Sci Rep 7 1 Genome-wide association study identifies novel susceptibility genes associated with coronary artery aneurysm formation in Kawasaki disease.

PLoS One 11 5 :e A genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki disease. PLoS Genet 5 1 :e Nat Genet 43 12 —6. A genome-wide association analysis reveals 1p31 and 2p Hum Genet 5 — Identification of KCNN2 as a susceptibility locus for coronary artery aneurysms in Kawasaki disease using genome-wide association analysis. J Hum Genet 58 8 —5. Common variants in the CRP promoter are associated with a high C-reactive protein level in Kawasaki disease.

Frontiers | Vasculitis Pathogenesis: Can We Talk About Precision Medicine? | Immunology

Pediatr Cardiol 36 2 — J Hum Genet 62 12 —9. PLoS One 12 9 :e BCL2L11 is associated with Kawasaki disease in intravenous immunoglobulin responder patients. Circ Genom Precis Med 11 2 :e Two new susceptibility loci for Kawasaki disease identified through genome-wide association analysis. Nat Genet 44 5 —5. A genome-wide association analysis identifies novel susceptibility loci for coronary arterial lesions in patients with Kawasaki disease. Transl Res 6 —5. Sci Rep A genome-wide association study identifies three new risk loci for Kawasaki disease. Nat Genet 44 5 — Identification of novel susceptibility loci for Kawasaki disease in a Han Chinese population by a genome-wide association study.

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PLoS One 6 2 :e Genetic variation in the SLC8A1 calcium signaling pathway is associated with susceptibility to Kawasaki disease and coronary artery abnormalities. Circ Cardiovasc Genet 9 6 — Prediction for intravenous immunoglobulin resistance by using weighted genetic risk score identified from genome-wide association study in Kawasaki disease. Circ Cardiovasc Genet 10 5 :e 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 8 8 :e Understanding the pathogenesis of Kawasaki disease by network and pathway analysis. Comput Math Methods Med