Seokchan Hong

Alpha-synuclein in gastric and colonic mucosa in Parkinson's disease: Limited role as a biomarker

Gastric and colonic alpha‐synuclein immunoreactivity has been reported in patients with Parkinsons disease (PD). However, enteric alpha‐synuclein also has been reported in healthy individuals.

Safety of resuming tumour necrosis factor inhibitors in patients who developed tuberculosis as a complication of previous TNF inhibitors

OBJECTIVES There is no consensus on whether restarting TNF inhibitors (TNFis) after treatment of an active tuberculosis (TB) infection caused by previous TNFi exposure is safe. In this study we sought to determine the safety of resuming TNFis in patients following TB treatment. METHODS The medical records of all patients (n = 683) that received TNFi treatment at a single rheumatology clinic between June 2003 and December 2012 were retrospectively reviewed. Among them, data from patients who developed active TB infection were collected and patient outcomes were evaluated for those who resumed TNFis after TB treatment. RESULTS Of 683 patients, 13 patients developed an active TB infection during TNFi treatment (4 on etanercept, 4 on adalimumab and 5 on infliximab). The median duration of TNFi treatment before TB infection was 20 months. TNFi treatment was reinitiated in six patients: four within 2 months after TB treatment and two after completion of TB treatment. Four patients reinitiated with the same TNFi, whereas two patients started with another TNFi. During a mean follow-up of 30.6 months, all six patients successfully completed TB treatment with no TB infection relapses. CONCLUSION Our results suggest that resuming TNFi therapy in patients following adequate TB treatment is safe, even before completion of TB treatment.

Clinicopathologic characteristics of IgG4-related retroperitoneal fibrosis among patients initially diagnosed as having idiopathic retroperitoneal fibrosis

Abstract Objective. The purpose of our study was to determine the number of IgG4-related retroperitoneal fibrosis (RPF) cases that were initially diagnosed as idiopathic RPF and to investigate clinical characteristics of IgG4-related RPF. Methods. We retrospectively reviewed the medical records of 41 RPF patients who were treated at our tertiary care medical center in South Korea between January 2000 and January 2013. We identified cases of 19 patients in which a diagnosis was made based on percutaneous biopsy or surgery and selected these cases for further analysis. Immunostaining for IgG4 and histopathologic examinations were performed for pathology specimens. Results. In the 19 RPF patients, more than 30 IgG4-positive plasma cells per specimen were identified in 9 cases with dense lymphoplasmacytic infiltrates, storiform fibrosis, or obliterative phlebitis (IgG4-related RPF group). The recurrence rate of IgG4-related RPF was significantly higher than that of idiopathic RPF (67% vs. 10%, p = 0.015). Initial and cumulative steroid dosages were not different between the two groups. Conclusions. We found that 47% of the patients initially diagnosed with idiopathic RPF showed IgG4-related RPF evidence according to the pathology and IgG4-related RPF patients showed higher recurrence rate than idiopathic RPF patients. We suggest that maintenance immunosuppressive therapy is required in IgG4-related RPF patients.

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.

High level of interleukin-32 gamma in the joint of ankylosing spondylitis is associated with osteoblast differentiation

BackgoundThe formation of bony spurs and ankylosis is a key pathognomic feature in ankylosing spondylitis (AS) and results in functional impairment. The aim of this study was to investigate the role of IL-32γ in osteoblast (OB) differentiation and its association with the pathogenesis of AS.MethodsThe concentration and expression of IL-32γ were evaluated in synovial fluid and tissue from patients with AS, rheumatoid arthritis (RA) and osteoarthritis (OA), using enzyme-linked immunosorbent assay and immunohistochemistry. To establish whether IL-32γ affects OB differentiation, we used calvarial cells of IL-32γ transgenic (TG) mice or wild-type (WT) mice. To elucidate the mechanism of osteoblastogenesis, levels of regulators were assayed in IL-32γ TG mice and in primary OBs after IL-32γ stimulation.ResultsThe IL-32γ levels were higher in the synovial fluid of AS patients compared with RA or OA patients and the expression of IL-32 was higher in AS synovia than in RA or OA synovia. Additional IL-32γ stimulation in precursor cells enhanced OB differentiation potentially and IL-32γ TG mice showed higher rates of OB differentiation than WT mice. IL-32γ reduced the expression of DKK-1, a negative regulator, in both WT precursor cells and human OBs and the constitutive expression of DKK-1 was suppressed in calvarial cells from IL-32γ TG mice.ConclusionsThe elevated level of IL-32γ in AS joint could enhance OB differentiation via DKK-1 suppression. Therefore, IL-32γ might be a putative molecular target to prevent the abnormal bone formation in AS.

Frequency of immunoglobulin G4-related aortitis in cases with aortic resection and their clinical characteristics compared to other aortitises

To identify the frequency of immunoglobulin G4 (IgG4)‐related aortitis in patients who undergo aorta surgery and are diagnosed by pathology as having chronic aortic inflammation and to compare IgG4‐related aortitis with other non‐infectious aortitises in terms of clinical characteristics.

TNF-α confers resistance to Fas-mediated apoptosis in rheumatoid arthritis through the induction of soluble Fas

AIMS Rheumatoid arthritis (RA) is a chronic inflammatory arthritis that is characterized by hyperplastic synovial tissue containing activated synovial fibroblasts. Contradictory findings in the apoptosis of fibroblast-like synoviocytes (FLS) have been described elsewhere, showing that RA FLS have an enhanced susceptibility to Fas (also known as CD95)-mediated apoptosis in vitro in contrast to the observed lack of apoptosis in the RA synovium in vivo. However, the potential mechanisms responsible for this discrepancy remain under investigation. The soluble form of Fas (sFas) was found to inhibit Fas-induced apoptosis by binding to Fas ligand (FasL), thereby preventing the interaction between FasL and membrane-bound Fas. MAIN METHODS We determined the levels of soluble FasL (sFasL) and sFas in patients with RA and the effects of proinflammatory mediators, including TNF-α, on the induction of apoptotic mediators in RA FLS. KEY FINDINGS The levels of sFasL and sFas were significantly elevated in the synovial fluids of RA patients compared with control subjects. In addition, we found that the sFas is substantially induced in RA FLS by TNF-α, which were abundantly present in the synovial fluid of RA. SIGNIFICANCE These findings suggest that TNF-α confers resistance to Fas-mediated apoptosis through sFas induction, which could explain the apparent resistance of RA synovial cells to apoptosis in vivo.

Interleukin-32 Gamma Stimulates Bone Formation by Increasing miR-29a in Osteoblastic Cells and Prevents the Development of Osteoporosis.

Interleukin-32 gamma (IL-32γ) is a recently discovered cytokine that is elevated in inflamed tissues and contributes to pathogenic features of bone in human inflammatory rheumatic diseases. Nevertheless, the role of IL-32γ and its direct involvement in bone metabolism is unclear. We investigated the molecular mechanism of IL-32γ in bone remodeling and the hypothetical correlation between IL-32γ and disease activity in osteoporosis patients. Transgenic (TG) mice overexpressing human IL-32γ showed reduced bone loss with advancing age, increased bone formation, and high osteogenic capacity of osteoblast compared to wild-type (WT) mice through the upregulation of miR-29a, which caused a reduction of Dickkopf-1 (DKK1) expression. IL-32γ TG mice were protected against ovariectomy (OVX)induced osteoporosis compared with WT mice. Decreased plasma IL-32γ levels were associated with bone mineral density (BMD) in human patients linked to increased DKK1 levels. These results indicate that IL-32γ plays a protective role for bone loss, providing clinical evidence of a negative correlation between IL-32γ and DKK1 as bone metabolic markers.

Mortality in patients with rheumatoid arthritis-associated interstitial lung disease treated with an anti-tumor necrosis factor agent.

Background/Aims To evaluate the impact on mortality of anti-tumor necrosis factor (anti-TNF) treatment of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Methods We retrospectively reviewed the medical records of 100 RA-ILD patients who visited our tertiary care medical center between 2004 and 2011, identified those treated with an anti-TNF agent, divided patients into non-survivor and survivor groups and evaluated their clinical characteristics and causes of death. Results A total of 24 RA-ILD patients received anti-TNF therapy, of whom six died (25%). Mean age at initiation of anti-TNF therapy was significantly higher in the nonsurvivor versus survivor group (76 years [range, 66 to 85] vs. 64 years [range, 50 to 81], respectively; p = 0.043). The mean duration of anti-TNF treatment in the non-survivor group was shorter (7 months [range, 2 to 14] vs. 23 months [range, 2 to 58], respectively; p = 0.030). The duration of anti-TNF therapy in all nonsurviving patients was < 12 months. Pulmonary function test results at ILD diagnosis, and cumulative doses of disease-modifying drugs and steroids, did not differ between groups. Five of the six deaths (83%) were related to lung disease, including two diffuse alveolar hemorrhages, two cases of acute exacerbation of ILD, and one of pneumonia. The sixth patient died of septic shock following septic arthritis of the knee. Conclusions Lung complications can occur within months of initial anti-TNF treatment in older RA-ILD patients; therefore, anti-TNF therapy should be used with caution in these patients.

Neutrophil-to-lymphocyte ratio is a reliable marker of treatment response in rheumatoid arthritis patients during tocilizumab therapy

Abstract Objective: To investigate the reliable markers reflecting treatment response better than the traditional inflammatory indices in patients with rheumatoid arthritis (RA) receiving tocilizumab therapy. Methods: A total of 58 RA patients treated with tocilizumab for more than six months from January 2013 to December 2014 were initially included. Flares were defined as events that required steroid dose escalation, intra-articular steroid injections, or switching tocilizumab to other biologic agents. The clinical and laboratory data were retrospectively collected from electronic medical records. Results: Of the 52 patients except for six patients who were excluded, 16 experienced flares, and 36 were stable during tocilizumab therapy. The C-reactive protein (CRP) level did not significantly differ between a stable state before flares and at flares. Compared with those at the preflare time point, erythrocyte sedimentation rate (ESR), and neutrophil to lymphocyte ratio (NLR) were significantly higher at flares; however, ESR levels (n = 9) were within the normal limit or decreased (n = 4) at flares. Interestingly, NLR increased at flares in all but one patient in the flare group. Conclusion: NLR is a more reliable marker than ESR or CRP for evaluating the disease activity in patients with RA during tocilizumab therapy.