Role of the IL-23/IL-17 Pathway in Rheumatic Diseases: An Overview

Interleukin-23 (IL-23) is a pro-inflammatory cytokine composed of two subunits, IL-23A (p19) and IL-12/23B (p40), the latter shared with Interleukin-12 (IL-12). IL-23 is mainly produced by macrophages and dendritic cells, in response to exogenous or endogenous signals, and drives the differentiation and activation of T helper 17 (Th17) cells with subsequent production of IL-17A, IL-17F, IL-6, IL-22, and tumor necrosis factor \u3b1 (TNF-\u3b1). Although IL-23 plays a pivotal role in the protective immune response to bacterial and fungal infections, its dysregulation has been shown to exacerbate chronic immune-mediated inflammation. Well-established experimental data support the concept that IL-23/IL-17 axis activation contributes to the development of several inflammatory diseases, such as PsA, Psoriasis, Psoriatic Arthritis; AS, Ankylosing Spondylitis; IBD, Inflammatory Bowel Disease; RA, Rheumatoid Arthritis; SS, Sjogren Syndrome; MS, Multiple Sclerosis. As a result, emerging clinical studies have focused on the blockade of this pathogenic axis as a promising therapeutic target in several autoimmune disorders; nevertheless, a greater understanding of its contribution still requires further investigation. This review aims to elucidate the most recent studies and literature data on the pathogenetic role of IL-23 and Th17 cells in inflammatory rheumatic diseases

Multiplex ligation-dependent probe amplification detection of an unknown large deletion of the CREB-binding protein gene in a patient with Rubinstein-Taybi syndrome

Rubinstein-Taybi syndrome is a rare autosomal dominant congenital disorder characterized by postnatal growth retardation, psychomotor developmental delay, skeletal anomalies, peculiar facial morphology, and tumorigenesis. Mutations in the gene encoding the cAMP response element-binding protein (CREB, also known as CREBBP or CBP) on chromosome 16p13.3 have been identified. In addition, some patients with low intelligence quotients and autistic features bear large deletions. Based on these observations, we used multiplex ligation-dependent probe amplification to search for large deletions affecting the CREBBP gene in a Rubinstein-Taybi syndrome patient. We identified a novel heterozygote deletion removing five exons (exons 17-21), encoding the histone acetyltransferase domain. We propose the use of multiplex ligation-dependent probe amplification as a fast, accurate and cheap test for detecting large deletions in the CREBBP gene in the sub-group of Rubinstein-Taybi syndrome patients with low intelligence quotients and autistic features

The in vitro addition of methotrexate and/or methylprednisolone determines peripheral reduction in Th17 and expansion of conventional Treg and of IL-10 producing Th17 lymphocytes in patients with early rheumatoid arthritis.

The aim of our study was to evaluate methotrexate (MTX) and methylprednisolone (MP) effect on peripheral Th17 and Treg subsets in patients with rheumatoid arthritis (RA). We enrolled 15 patients (10 early RA and 5 long-standing disease) with active RA and 10 age-matched healthy donors as controls. Frequencies of Th17 and Treg were quantified using flow cytometry before and after in vitro addition of MTX, MP or both drugs. Our results showed a reduction in the overall Th17 population followed by an increase in Th17 IL-10+ and Treg, after in vitro treatment of PBMCs with the drugs in patients with early RA. Long-standing disease patients showed a less evident increase in Treg cells and less enhancement of IL-10 Th17 cells. We suggest that the treatment with MTX and MP could ameliorate RA disease activity by normalizing the distribution/imbalance of Th17/Treg and indicate a new regulatory role of IL-17+ cells in RA patients. \ua9 2014, Springer-Verlag Berlin Heidelberg

AB0563 AORTIC ROOT DILATION IN ASSOCIATED WITH THE REDUCTION OF CAPILLARY DENSITY OBSERVED AT NAILFOLD CAPILLAROSCOPY IN SSC PATIENTS

Background:Systemic sclerosis (SSc) in a chronic autoimmune disease characterized by endothelial dysfunction and diffuse microangiopathy, leading to tissue ischemia and inducing fibrosis of skin and visceral organs. Furthermore, it was demonstrated the impairment of wall elasticity of large-medium vessels, such as aorta and its branches (1). SSc-related microangiopathy of vasa vasorum of the aortic wall could also be supposed. However no data on this hypothesis are available in literature.SSc microangiopathy may be easily studied at the nailfold by means of videocapillaroscopy. Indeed, capillaroscopic findings are representative of the microvascular damage caused by SSc troughout the body.Objectives:we aimed to investigate the presence of aortic root dilation, classical sign of aortic wall damage, in a cohort of SSc patients, and to correlate these findings with the capillaroscopic patterns (early, active, and late, according to Cutolo's classification (2)).Methods:we recruited 125 SSc patients (M/F: 14/111, mean age 55+/-12.7 years, median disease duration 11 years) in 3 Rheumatology Centres in Sicily, Italy, from January to December 2019.Transthoracic echocardiogram with aortic root diameter measurement was carried out in all patients. Moreover, videocapillaroscopy with identification of early, active, or late SSc patterns was performed in the whole case series. Patients with early SSc pattern formed the subgroup 1, while those with the active or late patterns (both characterized by the reduction of capillary density) the subgroup 2.Results:we identified 8 (6.4%) SSc patients with aortic root dilation (diameter > 35 mm). Their age and their frequencies of cardiovascular risk factors were similar to the whole series. Moreover, videocapillaroscopy showed 62 (49.6%) early, 47 (37.6%) active, and 16 (12.8%) late SSc patterns.Aortic root dilation was observed in only one patient in the subgroup 1 (1/62, 1.6%), and in 7 cases of the subgroup 2 (7/63, 11.1%); p=0.03.Conclusion:in this multicentre study, we found that aortic root dilation is significantly associated with the reduction of capillary density at nailfold capillaroscopy (active or late SSc patterns). On the basis of these findings, we might argue that SSc-related microangiopathy of vasa vasorum could contribute to aortic wall damage, at least in a subset of SSc patients.References:[1]Bartoloni E, Pucci G, Cannarile F, Battista F, Alunno A, Giuliani M, Cafaro G, Gerli R, Schillaci G. Central hemodynamics and arterial stiffness in systemic sclerosis. Hypertension 2016; 68:1504-1511. 2.Cutolo M, Matucci-Cerinic M. Nailfold capillaroscopy and classification criteria for systemic sclerosis. Clin Exp Rheumatol 2007; 25:663-665.Disclosure of Interests:Michele Colaci: None declared, Ylenia Dal Bosco: None declared, Claudia Schinocca: None declared, Maria Letizia Aprile: None declared, Giuliana Guggino Grant/research support from: Pfizer, Celgene, Speakers bureau: Celgene, Sandoz, Pfizer, Ilenia De Andres: None declared, Alessandra Azzurra Russo: None declared, Gianluca Sambataro: None declared, Domenico Sambataro: None declared, Lorenzo Malatino: None declare

Interleukin-9 Overexpression and Th9 Polarization Characterize the Inflamed Gut, the Synovial Tissue, and the Peripheral Blood of Patients With Psoriatic Arthritis

Objective. To investigate the expression and tis- sue distribution of Th9-related cytokines in patients with psoriatic arthritis (PsA). Methods. Quantitative gene expression analysis of Th1, Th17, and Th9 cytokines was performed in intestinal biopsy samples obtained from patients with PsA, HLA2B272positive patients with ankylosing spondylitis (AS), patients with Crohn’s disease (CD), and healthy controls. Expression and tissue distribu- tion of interleukin-23 (IL-23), IL-17, IL-22, IL-9, and IL-9 receptor (IL-9R) were evaluated by immunohisto- chemistry and confocal microscopy. Flow cytometry was used to study the frequency of Th9 cells among periph- eral blood, lamina propria, and synovial fluid mononuclear cells. The functional relevance of IL-9R expression on epithelial cells was assessed in functional in vitro studies. Th9 cells in synovial tissue from patients with PsA were also studied. Results. Subclinical gut inflammation in PsA patients was characterized by a clear Th17 and Th22, but not Th1, polarized immune response. Unlike AS and CD, a strong and significant up-regulation of IL-9 was observed in PsA gut, especially among infiltrating mononuclear cells, high endothelial venules, and Pan- eth cells. IL-92positive mononuclear cells were demon- strated to be in large part Th9 cells. IL-9 overexpression was accompanied by significant Paneth cell hyperplasia. Paneth cells strongly overexpressed IL-9R, and stimula- tion of epithelial cells, isolated from PsA patients, with IL-9 resulted in overexpression of a-defensin 5 and IL-23p19. Peripheral and synovial expansion of a4b71 Th9 cells was also observed in patients with PsA. Increased expression of IL-9 and IL-9R was also found in synovial tissue. Conclusion. Strong IL-9/Th9 polarization seems to be the predominant immunologic signature in patients in PsA

AB0184 ADHERENCE TO TREATMENT IN AN ITALIAN COHORT OF PATIENTS AFFECTED BY CHRONIC INFLAMMATORY ARTHROPATHIES TREATED WITH BIOLOGIC AGENTS

Background:The lack of adherence to treatment in patients affected by chronic diseases, such as rheumatic diseases, remains a relevant issue. Indeed, "inefficacy" or "intolerance" to therapies prescribed could hide a scarce compliance of a considerable percentage of patients.Objectives:We aimed to evaluate the adherence to treatment in a series of patients affected by chronic inflammatory arthropathies treated with biologic agents.Methods:We recruited 175 consecutive patients (M/F: 56/120; mean age 52.6±12.3 years) affected by rheumatoid arthritis (98), psoriatic arthropathy (45) or ankylosing spondylitis (32) treated with subcutaneous biologic agents. All patients completed the Morisky Medication Adherence Scales (MMAS-8)1, in order to estimate their adherence to therapy. Moreover, we achieved from all cases the Patient Global Assessment (PGA), the Visual Analogue Scale (VAS) for articular pain, the Health Assessment Questionnaire (HAQ), and the report of eventual adverse events.Results:Considering MMAS-8, 23/175 (13.1%) patients were low adherent to treatment (score <6), and 59/175 (33.7%) presented medium-grade adherence (score 6-7).Adherence to treatments tended to be higher in males (mean MMAS-8 7.3±1.1 vs. 6.9±1.6; p=0.073), while it was not associated with age, education level, type of articular disease, presence of adverse events, or treatment with the type of traditional or biologic DMARDs.Higher mean levels of PGA (51.3 vs. 38.8; p=0.012), VAS (52.6 vs. 44.3; p=0.08), and HAQ (0.9 vs. 0.5; p=0.001) was reported in low-adherent patients compared with full adherent subjects.Conclusion:Our study confirmed that the percentage of patients showing low adherence to therapy is relevant. Moreover, the association of lower adherence to treatments with higher values of the subjective clinimetric indexes suggests to pay attention to the apparent ineffectiveness or loss of efficacy of therapy.References:[1]Morisky DE et al. J Clin Hypertens 2008; 10:348–354.Disclosure of Interests:None declare

Abnormal F-18 Fluorodeoxyglucose Uptake of the Lung in Immunocompromised Lymphoma Patients in Complete Remission: Report of Two Cases and Revision of Literature

Limited data suggest that F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) may have a role in diagnosing infection. Here we present two cases of lymphoma patients in complete response (CR) who presented during follow-up dry cough and fever. Physical examination and serum evaluations were negative for lymphoma while whole body FDG-PET showed lung uptake which posed a differential diagnosis between relapse of lymphoma and an atypical pneumonia due to persistent lymphopenia. In both cases, cytology examination of sputum suggested Pneumocystis Jiroveci pneumonia (PJP). After appropriate antibiotic treatment, the follow-up examination showed complete resolution of the lung changes revealed by FDG-PET. False-positive results on FDG-PET were supposed to be due to the high uptake of FDG in non-neoplastic inflammatory cellular elements such as macrophages and lymphocytes. Our findings suggest that in cases of FDG-PET positive images in immunocompromised patients with previous hematologic disease, caution must be used, and differential diagnosis might include infections such as PJP in addition to relapse of disease