Yeon Sik Hong

Measurement of Interleukin-33 (IL-33) and IL-33 Receptors (sST2 and ST2L) in Patients with Rheumatoid Arthritis

The interleukin-33 (IL-33)/ST2 pathway has emerged as an intercellular signaling system that participates in antigen-allergen response, autoimmunity and fibrosis. It has been suggested that IL-33/ST2 signaling has been involved in the pathogenesis of rheumatoid arthritis (RA), because IL-33 and its receptor have been specifically mapped to RA synovium. The aim of this study was to determine the levels of IL-33 and sST2 in sera and synovial fluids in patients with RA. The serum level of IL-33 was significantly higher in patients with RA (294.9 ± 464.0 pg/mL) than in healthy controls (96.0 ± 236.9 pg/mL, P = 0.002). The synovial fluid level of IL-33 was significantly higher in RA patients than in osteoarthritis patients. The level of serum sST2 was higher in RA patients than in healthy controls (P = 0.042). A significant relationship was found between the levels of IL-33 and IL-1β (r = 0.311, P = 0.005), and IL-33 and IL-6 (r = 0.264, P = 0.017) in 81 RA patients. The levels of IL-33, sST2 and C-reactive protein decreased after conventional disease-modifying antirheumatic drugs treatment in 10 patients with treatment-naïve RA. Conclusively, IL-33 is involved in the pathogenesis of RA and may reflect the degree of inflammation in patients with RA.

Decreased production of interleukin-12 and interferon-gamma is associated with renal involvement in systemic lupus erythematosus.

Objective. To analyze the type 1 / type 2 cytokine balance in patients with systemic lupus erythematosus (SLE) according to the presence of renal disorder and activity status. Methods. We measured the serum levels of type 1 (IFN-γ, IL-12) and type 2 cytokines (IL-4, IL-10) as well as spontaneous and stimulated cytokine production from peripheral blood mononuclear cells (PBMC) in 40 patients with SLE. Results. Patients with lupus nephritis (LN) showed significantly lower levels of serum IL-12 and IFN-γ than those without LN. Production of IL-12 and IFN-γ by stimulated PBMC were also decreased in patients with LN. The circulating IL-12 correlated positively with IFN-γ, but inversely with IL-10. The SLEDAI scores correlated well with the ratio of IL-4/IFN-γ levels. Conclusion. The reduced production of IL-12 and IFN-γ and the resultant shift towards the type 2 cytokine phenotype may be associated with LN.OBJECTIVE To analyze the type 1/type 2 cytokine balance in patients with systemic lupus erythematosus (SLE) according to the presence of renal disorder and activity status. METHODS We measured the serum levels of type 1 (IFN-gamma, IL-12) and type 2 cytokines (IL-4, IL-10) as well as spontaneous and stimulated cytokine production from peripheral blood mononuclear cells (PBMC) in 40 patients with SLE. RESULTS Patients with lupus nephritis (LN) showed significantly lower levels of serum IL-12 and IFN-gamma than those without LN. Production of IL-12 and IFN-gamma by stimulated PBMC were also decreased in patients with LN. The circulating IL-12 correlated positively with IFN-gamma, but inversely with IL-10. The SLEDAI scores correlated well with the ratio of IL-4/IFN-gamma levels. CONCLUSION The reduced production of IL-12 and IFN-gamma and the resultant shift towards the type 2 cytokine phenotype may be associated with LN.

Coenzyme Q10 ameliorates pain and cartilage degradation in a rat model of osteoarthritis by regulating nitric oxide and inflammatory cytokines.

Objective To investigate the effect of CoenzymeQ10 (CoQ10) on pain severity and cartilage degeneration in an experimental model of rat osteoarthritis (OA). Materials and Methods OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA) to the knee. Oral administration of CoQ10 was initiated on day 4 after MIA injection. Pain severity was assessed by measuring secondary tactile allodynia using the von Frey assessment test. The degree of cartilage degradation was determined by measuring cartilage thickness and the amount of proteoglycan. The mankin scoring system was also used. Expressions of matrix metalloproteinase-13 (MMP-13), interleukin-1β (IL-1β), IL-6, IL-15, inducible nitric oxide synthase (iNOS), nitrotyrosine and receptor for advanced glycation end products (RAGE) were analyzed using immunohistochemistry. Results Treatment with CoQ10 demonstrated an antinociceptive effect in the OA animal model. The reduction in secondary tactile allodynia was shown by an increased pain withdrawal latency and pain withdrawal threshold. CoQ10 also attenuated cartilage degeneration in the osteoarthritic joints. MMP-13, IL-1β, IL-6, IL-15, iNOS, nitrotyrosine and RAGE expressions were upregulated in OA joints and significantly reduced with CoQ10 treatment. Conclusion CoQ10 exerts a therapeutic effect on OA via pain suppression and cartilage degeneration by inhibiting inflammatory mediators, which play a vital role in OA pathogenesis.

The change of bone mineral density according to treatment agents in patients with ankylosing spondylitis

OBJECTIVES The aim was to access the effects of treatment on bone mineral density (BMD) by treatment agents in patients with ankylosing spondylitis (AS). METHODS We analyzed clinical characteristics of 90 AS patients. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and x-ray of lumbar spine (L-spine) and sacroiliac joint were included in the baseline assessment. The BMDs of right femur and L-spine were measured annually using dual x-ray absorptiometry (DXA). The patients were divided into one of the following four groups by agents exposed for the follow-up period: conventional treatment, bisphosphonate, anti-TNF-α agent or bisphosphonate + anti-TNF-α agent. We evaluated the changes of BMD according to treatment groups. RESULTS The average age of disease onset was 30 years and the mean disease duration was 8.2 years. The patients who were assigned to the groups of conventional treatment, bisphosphonate, anti-TNF-α agents and bisphosphonate + anti-TNF-α agents were 40, 20, 19 and 11. BMDs values of both L-spine and femur showed tendencies to the most increase in the group treated with concurrent bisphosphonate and anti-TNF-α agent. However, the change of BMD by treatment agents was significant different only in trochanter (P = 0.001). In patients without syndesmophyte, there was significant difference of BMD change in both L-spine and total proximal femur (P = 0.001, 0.004). The BMD change of trochanter was correlated with the reductions of ESR and CRP (r = 0.239, P = 0.035 and r = 0.233, P = 0.040). CONCLUSIONS The BMDs of AS patients increased more by the treatment of concurrent bisphosphonate and anti-TNF-α agents. The gain of bone mass was associated with the reduction of inflammation.

Clinical and Radiographic Features of Adult-onset Ankylosing Spondylitis in Korean Patients: Comparisons between Males and Females

The objective of this study was to investigate clinical and radiographic features and gender differences in Korean patients with adult-onset ankylosing spondylitis. Multicenter cross-sectional studies were conducted in the rheumatology clinics of 13 Korean tertiary referral hospitals. All patients had a confirmed diagnosis of ankylosing spondylitis according to the modified New York criteria. Clinical, laboratory, and radiographic features were evaluated and disease activities were assessed using the Bath ankylosing spondylitis disease activity index. Five hundred and five patients were recruited. The male to female ratio was 6.1:1. Average age at symptom onset was 25.4±8.9 yr and average disease duration was 9.6±6.8 yr. Males manifested symptoms at a significantly earlier age. HLA-B27 was more frequently positive in males. Hips were more commonly affected in males, and knees in females. When spinal mobility was measured using tragus-to-wall distance and the modified Schobers test, females had significantly better results. Radiographic spinal changes, including bamboo spine and syndesmophytes, were more common in males after adjustment of confounding factors. In conclusion, we observed significant gender differences in radiographic spinal involvement as well as other clinical manifestations among Korea patients with adult-onset ankylosing spondylitis. These findings may influence the timing of the diagnosis and the choice of treatment.

The Effects of Antihypertensive Drugs on Bone Mineral Density in Ovariectomized Mice

The effects of several antihypertensive drugs on bone mineral density (BMD) and micro-architectural changes in ovariectomized (OVX) mice were investigated. Eight-week-old female C57/BL6 mice were used for this study. Three days after ovariectomy, mice were treated intraperitoneally with nifedipine (15 mg/kg), telmisartan (5 mg/kg), enalapril (20 mg/kg), propranolol (1 mg/kg) or hydrochlorothiazide (12.5 mg/kg) for 35 consecutive days. Uterine atrophy of all mice was confirmed to evaluate estrogen deficiency state. BMD and micro-architectural analyses were performed on tibial proximal ends by micro-computed tomography (micro-CT). When OVX mice with uterine atrophy were compared with mice without atrophy, BMD decreased (P < 0.001). There were significant differences in BMD loss between different antihypertensive drugs (P = 0.005). Enalapril and propranolol increased BMD loss in mice with atrophied uteri compared with control mice. By contrast, thiazide increased BMD in mice with uterine atrophy compared with vehicle-treated mice (P = 0.048). Thiazide (P = 0.032) and telmisartan (P = 0.051) reduced bone loss and bone fraction in mice with uterine atrophy compared with the control. Thiazide affects BMD in OVX mice positively. The reduction in bone loss by thiazide and telmisartan suggest that these drugs may benefit menopausal women with hypertension and osteoporosis.

Grape seed proanthocyanidin extract-mediated regulation of STAT3 proteins contributes to Treg differentiation and attenuates inflammation in a murine model of obesity-associated arthritis.

Grape seed proanthocyanidin extract (GSPE) is a natural flavonoid that exerts anti-inflammatory properties. Obesity is an inflammatory condition and inflammatory cells and their secretion of pro-inflammatory molecules contribute to the pathogenesis of obesity. Rheumatoid arthritis (RA) is a chronic autoimmune disease that is characterized by inflammation of joints lined by synovium. Previously, we demonstrated that obesity augmented arthritis severity in collagen induced arthritis (CIA), a murine model of human RA. Here, we investigated whether oral administration of GSPE showed antiobesity and anti-arthritic effects in high-fat diet-induced obese (DIO) mice and in obese CIA mice, respectively. The pathophysiologic mechanisms by which GSPE attenuates weight gain and arthritis severity in vivo were also investigated. In DIO mice, GSPE administration significantly inhibited weight gain, reduced fat infiltration in liver and improved serum lipid profiles. The antiobesity effect of GSPE was associated with increased populations of regulatory T (Treg) cells and those of decreased Th17 cells. Decrease of Th17 cells was associated with significant inhibition of their key transcriptional factors, pSTAT3Tyr705 and pSTAT3Ser727. On the contrary, GSPE-induced Treg induction was associated with enhanced pSTAT5 expression. To identify the anti-arthritis effects of GSPE, GSPE was given orally for 7 weeks after type II collagen immunization. GSPE treatment significantly attenuated the development of autoimmune arthritis in obese CIA model. In line with DIO mice, GSPE administration decreased Th17 cells and reciprocally increased Treg cells by regulating STAT proteins in autoimmune arthritis model. The expressions of pro-inflammatory cytokines and nitrotyrosine in synovium were significantly inhibited by GSPE treatment. Taken together, GSPE functions as a reciprocal regulator of T cell differentiation – suppression of Th17 cells and induction of Tregs in both DIO and obese CIA mice. GSPE may act as a therapeutic agent to treat immunologic diseases related with enhanced STAT3 activity such as metabolic disorders and autoimmune diseases.

Urinary Bladder Involvement in Patients with Systemic lupus Erythematosus With Review of the Literature

Objectives To investigate the etiologies of urinary bladder involvement in patients with systemic lupus erythematosus (SLE), the clinicoradiologic features of gastrointestinal tract manifestations and clinical outcomes in patients with lupus cystitis accompanied by gastrointestinal manifestations. Methods We conducted a retrospective chart review on 413 patients with SLE. Patients were selected for review on the basis of tower urinary tract symptoms including urinary frequency, urgency and urinary incontinence. Radiologic studies were analyzed in patients with lupus cystitis. Results Ten consecutive patients, complicated with lower urinary tract symptoms, were identified. Underlying etiologies were as follows: lupus cystitis in five, neurogenic dysfunction secondary to transverse myelitis in three, cyclophosphamide-induced cystitis in one and tuberculous cystitis in one patient. All patients with lupus cystitis showed gastrointestinal manifestations, such as abdominal pain, nausea, vomiting and/or diarrhea during the periods of cystitis symptoms. In all patients with lupus cystitis, paralytic ileus was demonstrated on plain abdominal X-ray and ascites, bilateral hydroureteronephrosis and thickened bladder wall were identified on abdominal ultrasound or CT. Abdominal CT revealed bowel wall thickening in four of the five patients. The main sites of thickened bowel on abdominal CT were territory supplied by superior mesenteric artery. Two of five patients with lupus cystitis expired during the follow-up period. Conclusion Diverse etiologies may cause lower urinary tract symptoms in patients with SLE. Lupus cystitis is strongly associated with gastrointestinal involvement and abdominal CT can be a useful radiologic tool to investigate the gastrointestinal tract involvement in patients with lupus cystitis.

Increased serum alkaline phosphatase levels correlate with high disease activity and low bone mineral density in patients with axial spondyloarthritis

OBJECTIVES Recent studies report an association between serum alkaline phosphatase (ALP) levels and inflammation. The present study examined the relationship between ALP and disease activity, bone mineral density (BMD), and radiological damage in axial spondyloarthritis (SpA). METHODS A total of 115 patients who fulfilled the ASAS axial SpA criteria were enrolled. Serum ALP, bone-specific ALP (BALP), serum cross-linked telopeptide of type-I collagen (sCTX), and inflammatory markers were measured. Clinical parameters, BMD, grade of sacroiliitis, and the modified Stoke AS Spinal Score (mSASSS) were also assessed. The Ankylosing Spondylitis Disease Activity Score (ASDAS) was also calculated. The associations between serum ALP, disease activity score, BMD, and radiologic damage were evaluated. RESULTS The mean serum ALP level was 77 ± 26 U/l. Serum ALP levels increased in 14 patients (13%). Serum ALP levels increased along with ASDAS-CRP after adjusting for age and sex (p = 0.004), and were significantly correlated with ASDAS-ESR and ASDAS-CRP (p = 0.001 and p < 0.001, respectively), negatively correlated with BMD in the lumbar spine and femoral neck (p = 0.003 and 0.046, respectively), and positively correlated with sacroiliitis grade and the mSASSS (p < 0.001 and p < 0.002, respectively). BALP and sCTX were not associated with disease activity or BMD. Multivariate analysis showed that serum ALP was independently associated with ASDAS-CRP (p = 0.010). CONCLUSIONS Increased serum ALP levels were associated with high disease activity, low BMD, and higher structural damage scores in SpA patients.

Trabecular bone score as an assessment tool to identify the risk of osteoporosis in axial spondyloarthritis: a case–control study

Objectives To compare the trabecular bone score (TBS) between patients with axial spondyloarthritis (axSpA) and matched normal controls and identify risk factors associated with a low TBS. Methods TBS and BMD were assessed in the two groups (axSpA and control) using DXA. Osteoporosis risk factors and inflammatory markers were also assessed. Disease activity and radiographic progression in the sacroiliac joint and spine were evaluated in the axSpA group. Multivariate linear regression analysis was performed to identify risk factors associated with TBS. Results In the axSpA group, 248 subjects were enrolled; an equal number of age- and sex-matched subjects comprised the control group. The mean TBS was 1.43 (0.08) and 1.38 (0.12) in the control and axSpA groups, respectively (P < 0.001); BMD at the lumbar spine did not differ between the two groups. The TBS was negatively correlated with ESR and CRP levels in the axSpA group only (P < 0.001 and P = 0.007, respectively). Syndesmophytes in the axSpA group was associated with lower TBS (P < 0.001) but higher lumbar BMD (P = 0.021) vs controls. In the multivariate analyses, ESR, CRP and spinal radiographic progression were significantly associated with TBS. Conclusion TBS assessments revealed poor bone quality in patients with axSpA compared with the matched controls. In axSpA, systemic inflammatory markers were negatively correlated with TBS and spinal radiographic progression and inflammatory markers were independently correlated with low TBS. TBS may, therefore, be a useful clinical tool to identify the risk of osteoporosis in patients with axSpA.