Min Wook So

Interleukin-34 produced by human fibroblast-like synovial cells in rheumatoid arthritis supports osteoclastogenesis.

IntroductionInterleukin-34 (IL-34) is a recently defined cytokine, showing a functional overlap with macrophage colony stimulating factor (M-CSF). This study was undertaken to address the expression of IL-34 in rheumatoid arthritis (RA) patients and to investigate its regulation and pathogenic role in RA.MethodsIL-34 levels were determined in the RA synovium, synovial fluid (SF) and fibroblast-like synovial cells (FLS) by immunohistochemistry, real-time PCR, enzyme-linked immunosorbent assay and immunoblotting. RA activity was assessed using Disease Activity Score 28 (DAS28) activity in the plasma collected at baseline and one year after treatment. Conditioned media (CM) were prepared from RA FLS culture with tumor necrosis factor alpha (TNFα) for 24 hours and used for functional assay.ResultsIL-34 was expressed in the synovium, SF, and FLS from RA patients. The production of IL-34 in FLS was up-regulated by TNFα in RA samples compared with osteoarthritis (OA) patients. Importantly, the preferential induction of IL-34 rather than M-CSF by TNFα in RAFLS was mediated by the transcription factor nuclear factor kappa B (NF-κB) and activation of c-Jun N-terminal kinase (JNK). IL-34 elevation in plasma from RA patients was decreased after the administration of disease-modifying anti-rheumatic drugs (DMARDs) in accordance with a decrease in DAS28. CM from RAFLS cultured with TNFα promoted chemotactic migration of human peripheral blood mononuclear cells (PBMCs) and subsequent osteoclast (OC) formation, effects that were attenuated by an anti-IL-34 antibody.ConclusionsThese data provide novel information about the production of IL-34 in RA FLS and indicate that IL-34 is an additional osteoclastogenic factor regulated by TNFα in RA, suggesting a discrete role of IL-34 in inflammatory RA diseases.

Idiopathic Inflammatory Myopathy Associated with Malignancy: A Retrospective Cohort of 151 Korean Patients with Dermatomyositis and Polymyositis

Objective. To define the standardized incidence ratio (SIR) of malignancy and factors associated with malignancies in Korean patients with dermatomyositis (DM) and polymyositis (PM). Methods. The demographic, clinical, and laboratory features of 151 patients diagnosed with DM/PM were compared in patients with and without malignancies. Results. Malignancies were found in 23 of 98 patients with DM (23.5%) and in 2 of 53 with PM (3.8%). Lung cancer (8 patients) was the most common malignancy. Compared with the period-specific, sex-matched, and age-matched Korean population, the SIR for malignancy in patients with DM was 14.2 (95% CI 9.0–21.3). Univariate analysis showed that factors associated with malignancy included older age (p < 0.001), DM (p = 0.002), dysphagia (p < 0.001), the absence of interstitial lung disease (ILD; p = 0.001), and lower elevations in aspartate aminotransferase (p = 0.005) and lactate dehydrogenase concentrations (p < 0.001). Multivariate analysis showed that factors independently associated with malignancy included older age (per 10 years, OR 2.3, 95% CI 1.6–3.5, p < 0.001), DM (OR 5.9, 95% CI 1.3–26.2, p = 0.020), dysphagia (OR 2.6, 95% CI 1.2–6.6, p = 0.042), and the absence of ILD (OR 0.1, 95% CI 0.01–0.9, p = 0.040). Conclusion. DM was associated with a greater risk of concomitant malignancies, especially lung cancer, than PM. Independent factors associated with malignancies in patients with DM/PM were older age, the presence of dysphagia, and the absence of ILD.

Efficacy of Incentive Spirometer Exercise on Pulmonary Functions of Patients with Ankylosing Spondylitis Stabilized by Tumor Necrosis Factor Inhibitor Therapy

Objective. To evaluate the effect of combining incentive spirometer exercise (ISE) with a conventional exercise (CE) on patients with ankylosing spondylitis (AS) stabilized by tumor necrosis factor (TNF) inhibitor therapy by comparing a combination group with a CE-alone group. Methods. Forty-six patients (44 men, 2 women) were randomized to the combination group (ISE plus CE; n = 23) or the CE group (n = 23). The CE regimen of both groups consisted of 20 exercises performed for 30 min once a day. The ISE was performed once a day for 30 min. The trial duration was 16 weeks. Patients were assessed before and at the end of treatment by measuring the Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index (BASFI), chest expansion, finger to floor distance, pulmonary function measures, and 6-min walk distance. Results. Both groups improved significantly in terms of chest expansion (p < 0.01), finger to floor distance (p < 0.01), and BASFI (p < 0.05) after completing the exercise program. However, only the combination group showed significant improvements in the forced vital capacity (p < 0.05), total lung capacity (p < 0.01), and vital capacity (p < 0.05). Although this did not achieve statistical significance, the combination group was mildly superior to the CE-alone group in functional disability and pulmonary function measures. Conclusion. Combining ISE with a CE can provide positive results in patients whose AS has been clinically stabilized by TNF inhibitor therapy.

The effect of various disease-modifying anti-rheumatic drugs on the suppressive function of CD4+CD25+ regulatory T cells

Accumulating evidence suggests that defects in the function of CD4+CD25+ regulatory T cells (Tregs) are important in immune-mediated diseases such as rheumatoid arthritis. Here, we investigated the effects of various disease-modifying anti-rheumatic drugs (DMARDs) on Treg function. Tregs and CD4+CD25− effector T cells (Teffs) were isolated from peripheral blood mononuclear cells obtained from healthy adults. Isolated Tregs were cultured with the DMARDs methotrexate (MTX), sulfasalazine (SSZ), leflunomide (LEF), or infliximab (INF). We found that each DMARD had a different effect on Treg function. SSZ and LEF inhibited the anti-proliferative function of Tregs on cocultured Teffs and reduced Treg expression of Foxp3 mRNA, whereas MTX and INF did not.

Successful rituximab treatment of refractory hemophagocytic lymphohistiocytosis and autoimmune hemolytic anemia associated with systemic lupus erythematosus

Abstract High-dose steroids, immunosuppressants such as cyclophosphamide and cyclosporine, and high-dose intravenous immunoglobulin have all been used to control hemophagocytic lymphohistiocytosis (HLH) or autoimmune hemolytic anemia (AIHA) associated with systemic lupus erythematosus (SLE); however, some patients are refractory to treatment. Rituximab has successfully resolved many of the refractory manifestations of SLE. Here, we report a case of HLH and AIHA associated with SLE that was refractory or intolerable to conventional therapy, but was successfully treated with rituximab.

Interleukin-33 acts as a transcriptional repressor and extracellular cytokine in fibroblast-like synoviocytes in patients with rheumatoid arthritis.

The present study aimed to assess the functions of interleukin (IL)-33 in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). Enzyme-linked immunosorbent assays (ELISAs) were used to quantify interleukin (IL)-33 in plasma obtained from patients with RA and osteoarthritis (OA). To evaluate functions of intracellular IL-33, levels of inflammatory mediators and matric metalloproteinases (MMPs) were measured in RA FLS transfected with IL-33 small- interfering RNA (siRNA) or plasmids, and changes in the expression and regulation of nuclear factor kappaB (NF-κB) were determined using western blotting and reporter gene assays. In addition, to examine the extracellular effects of IL-33, IP10 and receptor activator of NF-κB ligand (RANKL) mRNA levels were measured after treatment with IL-33 and blocking antibodies to ST2, the IL-33 receptor. To evaluate whether extracellular IL-33 regulated osteoclastogenesis, human CD14(+) monocytes cocultured with IL-33-stimulated FLS were stained with tartrate-resistant acid phosphatase (TRAP). IL-33 levels were higher in plasma obtained from patients with RA than in those obtained from patients with OA. The expression levels of IL-33 were elevated in RA FLS that had been stimulated with poly I:C, IL-1β, and tumor necrosis factor (TNF)-α. Silencing of IL-33 increased the levels of pro-inflammatory molecules and MMPs, promoted inhibitor of kappaB (IκBα) degradation, and increased NF-κB activity; these effects were reversed in IL-33 plasmid-transfected FLS. Stimulation with exogenous IL-33 increased RANKL and IP-10 mRNA expression. These increases were blocked by anti-ST2 treatment. Furthermore, we confirmed that extracellular IL-33 stimulated the formation of TRAP(+) multinucleated osteoclasts through RA FLS. These results suggested that intracellular IL-33 acted as a transcriptional repressor of NF-κB, which may provide negative feedback against inflammatory responses, whereas, extracellular IL-33 functioned as an activator of osteoclastogenesis. Therefore, increased plasma IL-33 levels in patients with RA could be a possible biomarker to reflect the potential risks of bone erosion.

Immunoglobulin G4-related disease with lymphoplasmacytic aortitis mimicking Takayasu arteritis.

Immunoglobulin 4 (IgG4)Yrelated systemic disease, which is defined pathologically as lymphoplasmacytic infiltration by IgG4-positive plasma cells, involves multiple organs. It may result in autoimmune pancreatitis, sclerosing cholangitis, IgG4associated nephropathy, and interstitial pneumonia, mimicking the clinical manifestations of other infectious, inflammatory, and neoplastic diseases. Aortic lesions, such as noninfectious thoracic aortitis, inflammatory abdominal aortic aneurysms/ periaortitis, and idiopathic retroperitoneal fibrosis, may also be related to IgG4-related disease. In most patients, aortitis resulting from IgG4-related diseases predominantly involves the thoracic aorta, including the aortic arch and descending aorta; however, there have been no reports of IgG4-related disease presenting as stenosis of the branch vessels of thoracic aorta, similar to Takayasu arteritis. We describe a patient with lymphoplasmacytic aortitis associated with IgG4-related disease involving the carotid and subclavian arteries.

The Influence of Interleukin-32γ on Osteoclastogenesis with a Focus on Fusion-Related Genes

We previously reported that interleukin-32 gamma (IL-32γ) has a direct effect on osteoclast differentiation and activation in vitro in the context of receptor activator of NF-κB ligand (RANKL) co-stimulation. However, the stage of osteoclast differentiation at which IL-32γ exerts its effect was not determined. Here, we demonstrated that IL-32γ plays an important role in the fusion of preosteoclasts to yield multinuclear osteoclasts, particularly large osteoclasts. The synergistic effect of IL-32γ on RANKL-induced formation of multinuclear osteoclasts was readily apparent when cells were treated with IL-32γ at the fusion stage. In addition, we demonstrated that IL-32γ induced the expression of dendritic cell-specific transmembrane protein (DC-STAMP) and nuclear factor of activated T cells cytoplasmic 1 (NFATc1), and NFATc1 inactivation by cyclosporine treatment attenuated the effect of IL-32γ. These results indicate that IL-32γ is a potential mediator of osteoclast fusion, likely through up-regulation of NFATc1 and DC-STAMP.

Factors associated with acute gout attacks in normouricaemic gout patients receiving allopurinol: a retrospective study

Objective: To identify factors associated with acute gout attacks in normouricaemic gout patients receiving allopurinol. Methods: We reviewed the medical records of 860 patients with chronic gout who were treated with allopurinol at a single tertiary hospital between 2003 and 2009. Of these, 135 patients had serum urate concentrations ≤ 360 μmol/L (6 mg/dL). Patients whose serum urate concentrations exceeded 360 μmol/L (6 mg/dL) at least once during follow-up were excluded. Patients who experienced at least one acute attack during follow-up, despite normouricaemia [≤ 360 μmol/L (6 mg/dL)], were classified as the Attack group (n = 51). The others were classified as the Non-attack group (n = 84). Results: The gout disease duration was significantly longer in the Attack group than in the Non-attack group (p = 0.036). The presence of tophi and multiple joint involvement were associated with acute attacks in normouricaemic gout patients. Multivariate analysis showed that both the presence of tophi [odds ratio (OR) 4.16, 95% confidence interval (CI) 1.41–12.23, p = 0.010] and the number of involved joints (OR 1.51, 95% CI 1.05–2.17, p = 0.028) were independently associated with acute attacks in normouricaemic gout patients receiving allopurinol. Conclusion: The presence of tophi and multiple joint involvement were associated with acute attacks in normouricaemic gout patients receiving allopurinol.

AB0625 Survival and Prognostic Factors in Patients with Connective Tissue Disease-Associated Pulmonary Arterial Hypertension: Results from A Korean Nationwide Registry

Background Pulmonary arterial hypertension (PAH) is a major cause of mortality in connective tissue disease (CTD). Objectives The survival rates and mortality-predictive factors of a nationwide registry of Korean patients with CTD-PAH were determined. Methods Patients with CTD-PAH were enrolled between April 2008 and December 2012. Hemodynamic parameters and clinical data (WHO-functional class [FC], organ involvement, laboratory tests, and treatment agents) were recorded. Survival rates were calculated by using the Kaplan–Meier method. Mortality-associated factors were examined by Cox proportional hazards regression analysis. Results In total, 174 incident PAH cases (61 with systemic lupus erythematosus, 50 with systemic sclerosis, 10 with mixed CTD, 22 with rheumatoid arthritis [RA], and 31 with other CTDs) were diagnosed by right heart catheterisation or Doppler echocardiography. Of these, 25 (14%) died during the 3.8±2.7 year follow-up period after PAH diagnosis. The 1 and 3 year survival rates were 90.7% and 87.3%, respectively. Compared to the other CTD-PAHs, RA-PAH had the lowest survival rates (56% 3 year survival; p=0.022). Multiple regression analysis revealed that low DLCO, pleural effusion, and diabetes mellitus were poor prognostic factors (p=0.008, 0.04, and 0.009, respectively). Anti-UI-RNP antibody positivity was protective (p=0.022). In patients with WHO-FC III/IV, patients who received vasodilators had lower mortality than those who did not (p=0.038). Conclusions In Korean patients with CTD-PAH, the 3 year survival rate was 87%. Low DLCO, pleural effusion, and DM were independent poor prognostic factors. Anti-UI-RNP antibody was protective. Prompt PAH-specific vasodilator therapy may improve the survival of patients with severe CTD-PAH. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1271