Aca 2013 Abstract Export Plenary Session: Plenary Session 1: Novel aspect of therapeutics of autoimmune diseases

Vitamin D is a fat-soluble hormone that is responsible for calcium homeostasis. However, it has paracrine and immune-modulatory effects through the widespread presence of the vitamin D receptor (VDR) in many cells including macrophages, dendritic cells, B and T lymphocytes and neutrophils. VDR activation in these cells leads to transcription of gene products that initiate a cascade of anti-proliferative, pro-differentiating and immune-regulatory processes. Dendritic cells are likely to be the primary immune target of 1,25(OH)D, affecting its role in antigen processing and presentation. Overall, 1,25(OH)D appears to suppress cell-mediated (Th1 and Th17) processes, and promote a regulatory or tolerogenic environment that may act to ÔcontainÕ autoimmune pathological mechanisms. Thus a lack of vitamin D may exacerbate autoimmune pathology.

The largest number of studies with regards to vitamin D and autoimmune diseases has been done in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). There is evidence that low vitamin D levels may increase disease susceptibility to both SLE and RA. SLE patients with low 25(OH)D levels have lower bone density, and increased SLEDAI scores. In RA, low 25(OH)D levels have been found to be negatively correlated with disease activity e.g. as measured with the Disease Activity Score (DAS28). Low 25(OH)D values were also found in those not in remission or responding poorly to treatment. However, there have been no clinical trials formally looking at vitamin D supplementation in the prevention or treatment of rheumatological disorders.
012 NK cells sustain immune tolerance at human maternal-fetal interface
Z.G. Tian¹, B.Q. Fu¹, X.C. Li², R. Sun¹, H.M. Wei<sup>1


1</sup>University of Science & Technology of China, School of Life Sciences, Hefei, China
²Brigham and Women’s Hospital and Harvard Medical School, Transplant Research Center, Boston, USA

Natural killer (NK) cells are innate immune lymphocytes that can control several types of tumours and microbial infections. Current research highlights the fact that natural killer cells also act as regulatory cells to affect adaptive immune response. Interestingly, NK cells accumulate in large numbers at the maternal-fetal interface, but their exact roles in successful pregnancy remain poorly defined. Here, we provide evidence that TH17 cells and local inflammation can occur at the maternal-fetal interface during natural allogenic pregnancies. We found that decidual NK cells promote immune tolerance and successful pregnancy by dampening inflammatory TH17 cells via IFN-γ secreted by CD56^brightCD27⁺ NK subset. We also found that this NK cell-mediated regulatory response is lost in patients who experience recurrent spontaneous abortions, which results in a prominent TH17 response and extensive local inflammation. This local inflammatory response further impacts the regulatory function of NK cells, leading to the eventual loss of maternal-fetal tolerance. Thus, our data identify NK cells as key regulatory cells that sustain immune tolerance at the maternal-fetal interface by suppressing TH17-mediated local inflammation.

Genetic factors are hypothesized to play a role in the susceptibility to antiphospholipid syndrome (APS) based on several family studies in patients with antiphospholipid antibodies (aPL) and/or clinical manifestations of APS. The genetics of β2-glycoprotein I (β2GPI), one of the most representative target antigens of aPL, has been extensively studied. 247 Val/Leu polymorphism can affect the conformational change of β2-GPI and the exposure of the epitopes for aCL. We found that 247 Val was correlated with anti-β2-GPI production in patients with primary APS, and 247 Val may be important for β2-GPI antigenicity. STAT4 SNP in Japanese patients with SLE and/or APS. T allele frequencies in SLE and APS were significantly elevated compared with that in healthy controls. When analyzed only in primary APS patients, T allele frequency was further higher. BANK1, BLK and SNP in 1q25.1 region were associated with not only SLE but also APS in Japanese population. These results suggest that APS and SLE, in part, share a common genetic background.

Standard disease activity measures in rheumatoid arthritis such as the Disease Activity Score in 28 joints (DAS28) are based on evaluators and have high inherent inter-observer variability. Other commonly used simplified versions are improved mainly in the arithmetic. The other limitation is the dependency for blood tests on inflammatory indices, the result of which may not be readily available upon clinic visit. Moreover, patients cannot monitor their own disease activity at home, in a way similar to ambulatory blood pressure and home haemoglucostix monitoring in other chronic illnesses.

Patient-based disease activity score (PDAS1 [with erythrocyte sedimentation rate ESR] & PDAS2 [without ESR]) in rheumatoid arthritis (RA) are developed in an attempt to overcome these limitations. In the developmental cohort, the PDAS with ESR (PDAS1) and without ESR (PDAS2) achieved excellent fit with the DAS28. The results were validated in another validation cohort. The PDAS and DAS28 had similar sensitivity to change, determined using effect sizes and standardized response means.

Status and responder criteria of European League Against Rheumatism (EULAR) DAS28 had also been mapped to PDAS. Remission, low, moderate and high disease activities, good and moderate responses to treatment were determined. They have comparable agreement and performance to standard criteria based on DAS28 and Clinical Disease Activity Index (CDAI).

PDAS appears suitable for clinical decision-making, epidemiologic research, and clinical trials.
021 Introduction of Korean nationwide RA cohort and Clinical implication
Sang-Cheol Bae, MD, PhD, MPH
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Korea

A large national prospective cohort can be crucial in performing clinical research. In South Korea, KORean Observational study Network Arthritis (KORONA) has been established by Clinical Research Center for Rheumatoid Arthritis (CRCRA) at Hanyang University funded by the Ministry of Health and Welfare in 2008. KORONA has been investigated by using prospective protocol including patientsÕ demographics, clinical features, laboratory and radiologic data, health-related outcomes, treatment side effects, resource utilization, and health behaviors in 23 University Hospitals. CRCRA have implemented annual monitoring, auditing, staff training and provides standard operation protocol. Currently, 5,376 RA patients were enrolled and approximately 80% of their follow-ups are going on.

Prospective cohort study can provide the information that cross-sectional study or randomized clinical trials (RCTs) cannot provide and it also enables to reflect clinical practice. For example, it enables researchers to investigate how patientsÕ characteristics (i.e. genetic factors) could affect the disease outcomes and to investigate both research subjects that cannot be conducted by RCTs and excluded patients in RCTs (i.e. patients with old age or comorbidities who excluded in RCT). In addition, cohort study can reflect real clinical practice and provide long-term patients-oriented outcomes (PROs).

In this talk, I would like to introduce KORONA cohort and present the important results of our studies using this cohort.

Inhibition of the immuno proteasome has been recently demonstrated tohave a potential therapeutic effect especially in patients sufferingfrom SLE. Studies in experimental animal models for SLE proved to showthat the inhibition of the proteasome not only prevented thedevelopment of the disease, but also in animals with manifest SLEsyndromes showed a significant improvement in antibody titors andkidney function. Studies on the function of the inhibition of theproteasome revealed that specifically long-lived plasma cells will beaffected, and as more recently shown, that the interferon alphaproduction by plasmacytoid dendritic cells will be significantlyinhibited (H. Travis Ichikawa et al. Arthritis Rheum 2012, 64:493-503).Severe side effects observed in the experimental animal models wereacceptable. There was no major influence by the inhibition ofbortezomib on T cell function.

Multiple sclerosis (MS) causes neurological disability. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS. Human bone-marrow mesenchymal stem cells (hMSCs) possess anti-inflammatory and immunosuppressive effects. We studied whether hMSCs affect CD1d^highCD5⁺ regulatory B cells activity in EAE. EAE is induced in C57BL/6N mice by immunization with MOG_35-55 peptide. hMSCs are injected intravenously into EAE mice at day 3 and day 12 after first immunization. Mice were sacrificed at day 26. Immunohistochemistry of spinal cord, serum cytokines levels, production of cytokines by cultured splenic cells, and flow cytometry for splenic Th17 and CD1d^highCD5⁺ regulatory B cells were studied. We found that EAE mice with hMSCs treatment as day 3 and day 12 had reduced EAE scores from day 14 to 26 compared to EAE mice without hMSCs treatment, and reduced infiltration of inflammatory cells and demyelination in spinal cord. EAE mice with hMSCs treatment at day 3 and day 12 had 1) lower serum levels of IL-6, TNF-α (p<0.0005) and IL-17 (p<0.005 for day 3, p<0.0005 for day 12), 2) reduced splenic cell production and secretion of IL-6, TNF-α (p<0.05) and IL-17 (p<0.05), and increased splenic production of IL-10, 3) reduced splenic Th17 cells (p<0.05 for day 3, p<0.005 for day 12) and 4) increased CD1d^highCD5⁺ regulatory B cells (p<0.005) than EAE mice without hMSCs treatment. hMSCs treatment at day 3 and 12 suppresses EAE severity. The underlying mechanisms involve downregulation of Th17 cells and upregulation of CD1d^highCD5⁺ regulatory B cells activity.

Tumor necrosis factor-α (TNF-α) antagonists are effective in suppressing inflammation in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). However, it is debatable if they have favorable effects on the cardiovascular (CV) system. The use of surrogate end points instead of actual CV events may provide more evidence on whether rheumatic disease patients may benefit from potent anti-inflammatory treatment such as anti-TNF-α therapy on the prevention of premature atherosclerosis. Surrogate markers including carotid intima media thickness (cIMT) has been widely used to assess subclinical atherosclerosis; while pulse wave velocity (PWV) and aortic augmentation index (AIx) are the gold standards to assess arterial stiffness. Published data suggest that TNF-α blockers probably are effective in preventing or even reversing the progression of IMT in patients with RA, AS and PsA who are responding to treatment. With regards to arterial stiffness, PWV was either significantly reduced or remained unchanged in most studies following TNF-α antagonist treatment; nonetheless, most studies in RA reported significant improvement of PWV. In contrast, AIx remained unchanged in the majority of the studies. The balance of evidence suggests that TNF-α antagonists may have a beneficial effect on preventing the progression of subclinical atherosclerosis and arterial stiffness. Consequently, this may have a beneficial effect on CV risk. However, longer term cohort studies are needed to confirm these promising results.

Recurrent spontaneous abortion (RSA) is defined as two or more consecutive spontaneous abortions, which may occur at any stage of pregnancy. Among various causes of RSA, autoimmune abnormalities can play a relevant role - the most significantly implicated being antiphospholipid antibodies (aPL). However, in several cases, no evident explanation is found and recurred abortion is reported to be unexplained. A deeper insight into apparently unexplained RSA shows increasing evidences supporting also an alloimmunologic mechanism, a condition in which natural killer (NK) cells may play a relevant role when in too high concentrations. Given the poor understanding of the precise mechanisms underlying RSA and unexplained RSA, therapy so far has been empirical and not evidence based. Treatment modalities for RSA include aspirin, heparin, progesterone, prednisone and intravenous immunoglobulins (IVIGs). Different immunomodulatory effects have been reported for IVIG and, among others, antigen neutralization, Fc-receptor blockade and anti-idiotypic interactions, changes in distribution and function of T-cell subsets, antibodies to autoantigens and mild activation of complement. Furthermore, it is known that IVIGs affect cytokine production in T lymphocytes and monocytes/ macrophages, all mechanisms of potential benefit in RSA. Our study compared intravenous immunoglobulins (IVIG) and prednisone in treating pregnant women with a history of recurrent fetal loss in terms of live-birth rate and maternal and perinatal morbidity. The results of this study will be discussed.