Genital and Oral Microbiome and Behçet’s Disease Activity

BackgroundThe aetiopathogeneses of Behçet’s Disease (BD) remains elusive with multifactorial genetic and epigenetic factors resulting in multisystemic disease. Oral and genital ulceration are common and influences disease outcome. We hypothesised that dysregulation of genital and oral microbial communities contributes to BD disease activity. 153 BD patients’ samples, 70 matched oral and genital (Female: Male, 58:12; mean age, 42±13.9: 39.3±10.3), 12 unmatched samples; 16s rRNA sequencing utilised and V1/V2 and V3/V4 regions analysed. BD outcomes: oral and genital ulcer severity and BD activity scores, Psychological and Social Well-being scales, Headache Impact Test-6 (HIT-6) were included. All the analyses were performed with R software. ResultsThe alpha and beta diversity had anatomical specificity, with significant differences between genital and oral samples; p values<0.05 irrespective of presence or absence of ulcers. Interestingly, in the genital area Bacteroidota were present (G_U: 29% - 10%) and (G_nU: 27% - 14%) compared to less than 1% oral area of V1/V2 and V3/V4. Proteobacteria were uniquely present with (O_U: 9%) and (O_nU: 12%) in oral, and less than 0.01% in genital area for V3/V4 region. Gender anatomical specific communities were noted: females with genital ulcers Gardnerella, Lactobacillus, Atopobium were significantly increased compared to than males, with V3/V4 analysis indicating that Lactobacillus and Gardnerella were significantly increased by 20 times in females than males (p-adj <0.05). In contrast Peptoniphilus and Corynebacterium were significantly increased in males than females. Streptococcus was significantly increased with oral ulceration, while Veillonella was significantly decreased in patients without oral ulceration. Colchicine had a significant effect on the bacterial abundance irrespective of the presence or absence of ulceration. In this cohort, the WSAS (Work and Social Adjustment Scale) values were higher in active disease. ConclusionOur results suggest that dysregulated microbial communities occur in BD. V1/V2 demonstrates that during episodes of ulceration the pathogenic bacteria genus Escherichia-Shigella appear in both oral and genital ulcers. V3/V4 outcomes show that ulceration in both regions is assigned to genus; Lachnospiraceae, Saccharimonidales, Coriobacteriales. Streptococcus is related to the presence of oral ulcers, while Veillonella is presence when patients are ulcers free may be a useful marker of disease regression.

Beneficial Effects of Apremilast on Genital Ulcers, Skin Lesions, and Arthritis in Patients With Behçet’s Disease: A Systematic Review and Meta-Analysis

Objective This study aimed to determine the clinical efficacy of apremilast for oral ulcers, extra-oral manifestations, and overall disease activity in patients with Behçet’s disease (BD). Methods A systematic literature search was performed in PubMed, EMBASE, Cochrane Library, and Web of Science Core Collection. Studies assessing the treatment effects of apremilast in BD were included. The odds ratios (ORs) of being symptom free for individual manifestations and mean difference (MD) of Behçet’s Disease Current Activity Form (BDCAF) scores were calculated with 95% confidence intervals (CIs) at 12 and 24 weeks using a random-model meta-analysis. Results Of 259 screened articles, eight were included. After 12 weeks of apremilast treatment the OR of symptom-free was as followings: oral ulcers, 45.76 (95% CI, 13.23–158.31); genital ulcers, 4.56 (95% CI, 2.47–8.44); erythema nodosum, 3.59 (95% CI, 1.11–11.61); pseudofolliculitis, 2.81 (95% CI, 1.29–6.15); and arthritis, 3.55 (95% CI, 1.71–7.40). Furthermore, BDCAF scores at 12 weeks were significantly reduced (MD=−1.38; −1.78 to −0.99). However, the proportion of oral-ulcer free patients increased at 24 weeks (OR=14.88; 4.81 to 46.07). Conclusion The currently accumulated data indicates an improvement in mucocutaneous and articular symptoms by short-term apremilast treatment in patients with BD.

A Young Woman With Vessel Dissection and Brainstem Lesions

A 21-year-old woman with baseline depression, 1-year history of recurrent, painful, oral and vaginal ulcers, and cellulitis had a new, severe, acute-onset, left posterior headache with left shoulder pain. On neurologic examination, she had mild right oculomotor and abducens nerve weakness and marked left upper extremity and moderate left lower extremity upper motor neuron–type paresis. Initial brain magnetic resonance imaging showed acute ischemia involving the right pons, right midbrain, right cerebral peduncle, and internal capsule, extending into the right diencephalic region. Neck computed tomography angiography identified a right vertebral artery dissection at the C3 level. Cerebrospinal fluid analysis showed a marked neutrophilic pleocytosis with a reported “high” white blood cell count. HLA-B51 testing was positive. Biopsies of her ulcers indicated nonspecific inflammation with no infectious sources. Her severe headache preceding the manipulations, along with recurrent, painful, oral and genital ulcers (recurrent aphthous stomatitis), cerebrospinal fluid pleocytosis, and brainstem involvement after a vertebral artery dissection, raised concern for Behçet syndrome and eventually neurologic involvement of Behçet syndrome. Recurrent corticosteroid-responsive oral ulcers plus recurrent genital ulcers and skin lesions (cellulitis) fulfill the criteria for Behçet syndrome, with possible neurologic involvement (neuro-Behçet syndrome). The positive HLA-B51 testing was consistent with the diagnosis of Behçet syndrome. Treatment was initiated with low-dose aspirin and intravenous methylprednisolone, after which her neurologic status started to improve. Oral prednisone and azathioprine were added for long-term treatment. At age 25 years, she discontinued azathioprine because she planned pregnancy. At age 27 years, she started having recurrence of oral and genital ulcers, along with axillary ulcerative skin lesions. New-onset diplopia and left-sided weakness also developed before corticosteroid and azathioprine could be reinitiated. Magnetic resonance imaging of the brain showed a new left pontine and cerebellar peduncle lesion with subtle contrast enhancement. Intravenous methylprednisolone was initiated, followed by reinitiation of oral prednisone and the azathioprine regimen for long-term maintenance immunotherapy. The prednisone was slowly tapered after 3 months. The final diagnosis for this patient was relapsing neuro-Behçet syndrome because she had 2 recurrent neurologic episodes associated with 1) vertebral artery dissection and 2) brainstem involvement. If she were to have further relapses, the plan was to administer a tumor necrosis factor-α‎ inhibitor. The case of this patient highlights 3 aspects of Behçet syndrome: 1) diagnosis of systemic Behçet syndrome is made on clinical grounds only, but even if the diagnostic criteria are not fulfilled, once neuro-Behçet syndrome develops, treatment should be initiated to curtail significant morbidity; 2) although rare, arterial involvement in neuro-Behçet syndrome should be recognized; and 3) there are notable sex-dependent factors in the evolution of Behçet syndrome.

Pulmonary artery thrombosis as the first presentation of Behçet’s syndrome: a case report and review of the literature

Background Behçet’s syndrome is a type of systemic chronic vasculitis of unknown etiology, frequently characterized by recurrent oral and genital ulcers and uveitis. It is less commonly characterized by arthritis and skin, vascular, and gastrointestinal involvements. Behçet’s syndrome affects various sizes of vessels by perivascular infiltration and vasculitis. Unlike other classic types of vasculitis, Behçet’s syndrome patients can present with both arterial and venous involvement. Although vascular Behçet’s syndrome is found in only around 15% of Behçet’s syndrome patients, it is the major cause of morbidity and mortality among them. Furthermore, although deep venous thrombosis has high incidence in Behçet’s syndrome patients, pulmonary artery thrombosis is an uncommon complication. Combining the findings of this and previous case reports of pulmonary artery thrombosis in Behçet’s syndrome patients, we sought to determine the best treatment options for pulmonary artery thrombosis in Behçet’s syndrome patients. Case presentation We present the case of a 22-year-old Arabian male who was admitted to an emergency department with acute chest pain, dyspnea, and hemoptysis for 2 weeks. He gave a long history of recurrent oral and genital ulcers for the last 4 months but without seeking medical advice. Spiral computed tomography showed arterial filling defects with a pulmonary nodule for which the presence of a pulmonary artery aneurysm ruled out. The lung perfusion scan showed multiple pulmonary perfusion defects. After excluding common infectious diseases such as tuberculosis and brucellosis, a diagnosis of Behçet’s syndrome with pulmonary artery thrombosis was made. Steroids with enoxaparin were initiated. The patient was discharged later on prednisolone (tapering dose) with adalimumab and apixaban. He was on regular follow-up for the next 9 months. Conclusions Vascular involvement in Behçet’s syndrome is a major contributor to morbidity and mortality of Behçet’s syndrome patients. Consequently, early detection of vascular involvement has a major impact on the prognosis of patients with Behçet’s syndrome.

POS1358 THE EFFECTS AND SAFETY OF APREMILAST AND CYTOKINE EXPRESSION IN BEHCET’S DISEASE PATIENTS

Background:Apremilast, the small-molecule phosphodiesterase (PDE) -4 inhibitor, was approved for the treatment of recurrent oral ulcers associated with Behcet’s disease (BD) in Japan from September 2019, following the success of the phase 3 RELIEF study (1). However, the efficacy of apremilast on domains other than oral ulcers in BD patients is unclear. On the other hand, it has been reported that apremilast may decrease the production of proinflammatory cytokine and increase the production of anti-inflammatory mediators in psoriasis (PS) and psoriatic arthritis (PsA) (2).Objectives:To evaluate the effects and safty of apremilast on clinical symptoms and the changing of serum cytokine expression.Methods:BD patients who had treated with apremilast for active oral ulcers were included in the study. We investigated the improvement rate of oral and genital ulcers, skin lesions, arthritis. In addition, serum cytokines (IFN-γ, IL-10, IL-8, and TNF-α) before and after apremilast treatment were measured using a multiplex immunoassay (Luminex Assay, R&D Systems).Results:Fourteen patients (3 males and 11 females) were enrolled in this study. The mean age was 46.6 ± 13.0 years and the mean duration of disease was 10.2 ± 8.8 years. All patients had active oral ulcers, five had genital ulcers, six had skin lesions, and four had arthritis. Three months after the treatment with apremilast, oral ulcers improved in 13 patients (92.9%). The improvement rates of genital ulcers, skin lesions and arthritis were 60%, 25% and 25%, respectively. Changes in serum cytokines were different from those previously reported in PS. Adverse events were gastrointestinal symptoms such as nausea and diarrhea in 6 patients and sensorineural deafness in 1 patient. Medication was reduced in 2 patients, and discontinued in 1 patient due to nausea and diarrhea.Conclusion:Apremilast is useful not only for oral ulcers, but also for other lesions in BD patients. The effect of apremilast for other domain such as genital ulcers, skin lesions, arthritis was not comparable to that of active oral ulcers. Additionally, BD may have different cytokine profile from PS and PsA.References:[1]Hatemi G, Mahr A, Ishigatsubo Y, et al. Trial of Apremilast for Oral Ulcers in Behcet’s Syndrome. N Engl J Med. 2019;381(20):1918-28[2]Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochem Pharmacol. 2012;83(12):1583-1590Disclosure of Interests:None declared