Effectiveness and safety of adalimumab in patients with intestinal Behçet's disease: a real-world prospective observational study in South Korea.

BACKGROUND: Intestinal Behçet's disease (BD) is characterized by typical gastrointestinal ulcers in patients with BD followed by complications such as bleeding, perforation and fistula. Biologic agents are currently under active investigation to delay the disease course. Various data regarding infliximab are available, but there is relatively lack of data regarding adalimumab. METHODS: This was a multicenter, real-world prospective observational study to evaluate the effectiveness and safety of adalimumab in intestinal BD. The primary endpoint was disease activity at each follow up, including disease activity index for intestinal Behçet's disease (DAIBD), serum C-reactive protein (CRP) level, and endoscopic findings. The secondary endpoint was the incidence of adverse drug reactions (ADRs). RESULTS: A total of 58 patients were enrolled and 8 of them were excluded. Adverse events were reported in 72.0% of patients with 122 events. ADRs were reported in 24.0% with 28 events. For adverse events, arthralgia was most commonly reported (13.1%: 16/122) and only one experienced critical adverse event (0.82%, 1/122: death due to stroke). On multivariable regression analysis, a longer disease duration was significantly associated with decreased ADRs [Odds ratio 0.976 (0.953-0.999, 95% CI); p = 0.042]. Clinical response rates as assessed by DAIBD were 90.9% at Week 12 and 89.7% at Week 56, respectively. The mean serum CRP level at baseline was significantly decreased after 12 weeks (3.91 ± 4.93 to 1.26 ± 2.03 mg/dL; p = 0.0002). CONCLUSION: Adalimumab was found to be safe and effective in Korean patients with intestinal BD. A longer disease duration was significantly associated with decreased ADRs.

COVID-19 vaccination-related small vessel vasculitis with multiorgan involvement.

Since its first outbreak in 2019, coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2, has been ongoing, and the pandemic is not over yet. Vaccines developed against COVID-19 have been approved and widely used since 2020; however, vaccine safety concerns need to be addressed. Autoimmune symptoms have been reported as a side effect of many COVID-19 vaccines. In particular, several cases of COVID-19 vaccine-induced vasculitis have recently been reported. Herein, we report the case of a 77-year-old woman who developed small-vessel vasculitis with multiorgan involvement after receiving the BNT162b2 COVID-19 vaccine (Pfizer and BioNTech, New York City, NY, USA).

Associations of Neutrophil-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio and Monocyte-to-Lymphocyte Ratio with Osteoporosis and Incident Vertebral Fracture in Postmenopausal Women with Rheumatoid Arthritis: A Single-Center Retrospective Cohort Study.

Background and Objectives: We investigated whether nutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphoycte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) are associated with the presence of osteoporosis (OP) and vertebral fractures in patients with rheumatoid arthritis (RA). Materials and Methods: This retrospective cohort study included 413 postmenopausal patients with RA and 200 healthy controls who underwent dual-energy X-ray absorptiometry (DEXA) between January 2005 and December 2017. DEXA examination data were defined as the index date, and all laboratory values were measured within one month from the index date. OP was defined as a T-score < −2.5, and incident vertebral fractures were defined as the first occurrence of non-traumatic fractures after the index date. NLR, PLR, and MLR measures were dichotomized by a median split (low vs. high). Results: The median NLR, PLR, and MLR in RA patients were significantly higher than those in controls. The frequencies of OP of the lumbar spine, hip, and either site in postmenopausal patients with RA were 24.7%, 15.5%, and 32%, respectively, and were significantly higher than those in controls. After adjusting for confounding factors, a high baseline NLR was significantly associated with OP at either site (OR = 1.61, p = 0.041). In addition, high baseline NLR (OR = 2.11, p = 0.025) and PLR (OR = 2.3, p = 0.011) were related with the presence OP at hip. During the follow-up period, 53 (12.8%) patients with RA developed vertebral fractures incidentally. In multivariable Cox regression models, a high baseline NLR (HR = 4.72, p < 0.001), PLR (HR = 1.96, p = 0.024), and MLR (HR = 2.64, p = 0.002) were independently associated with a higher risk of incidental vertebral fractures. Conclusions: Our data suggest that NLR, PLR, and MLR can be used as potential markers of systemic bone loss among individuals with RA.

Platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio as potential makers for digital ulcers and interstitial lung disease in patients with systemic sclerosis: cross-sectional analysis of data from a prospective cohort study.

In this study, we aimed to investigate the association of platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) with clinical manifestations in patients with systemic sclerosis (SSc). We conducted a cross-sectional analysis of data collected from a cohort study of 114 female patients with SSc and of 304 age-matched, healthy, female controls recruited from a tertiary rheumatology center. Patients with digital ulcers (DU) included those with either active or healed ulcers. Interstitial lung disease (ILD) was diagnosed on detection of diffuse ground-glass opacity or pulmonary fibrosis on chest X-ray or on high-resolution computed tomography. Patients with SSc had significantly higher PLR and NLR than ealthy controls. Of 114 patients with SSc, 35 (30.7%) and 54 (47.4%) patients had DU (active: 12, healed: 23) and ILD, respectively. PLR and NLR in SSc patients with concurrent DU or ILD were significantly higher than that in those without these respective complications. The PLR (OR = 1.008, 95% CI 1.002-1.015), but not the NLR, was independently associated with the presence of DU in SSc patients, based on multivariable logistic regression models. Additionally, both PLR (OR = 1.008, 95% CI 1.001-1.014) and NLR (OR = 1.515, 95% CI 1.066-2.155) correlated independently with the presence of ILD. However, both the PLR and NLR showed no significant association with the modified Rodnan skin score, pulmonary arterial hypertension, and gastrointestinal involvement. Our results suggest that PLR and NLR could be considered as potential biomarkers of DU and ILD, in patients with SSc.

Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio as predictors of 12-week treatment response and drug persistence of anti-tumor necrosis factor-α agents in patients with rheumatoid arthritis: a retrospective chart review analysis.

Data are scarce regarding the association of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) with treatment response and persistence of anti-TNF-α agents in patients with rheumatoid arthritis (RA). Thus, we investigated whether baseline NLR and PLR could predict 12-week treatment response and long-term persistence of anti-TNF-α agents in RA patients. This is a retrospective chart review analysis of 82 women with RA who started anti-TNF-α agents as the first-line biologic therapy and 328 healthy age-matched women. RA patients were divided into high and low baseline NLR or PLR subgroups using the median split. European League against Rheumatism (EULAR) treatment response was evaluated at 12 weeks. RA patients had significantly higher NLR and PLR than controls. High baseline NLR and PLR groups showed higher 12-week EULAR non-response rate than low NLR (30% vs 7.1%, p = 0.01) and PLR groups (27.5% vs 9.5%, p = 0.047), respectively. After adjusting for confounding factors, high baseline NLR (OR 5.57, p = 0.014) and PLR (OR 4.24, p = 0.04) were significantly associated with a higher risk of EULAR non-response at 12 weeks. During the study period, 47 (57.3%) RA patients (lack of efficacy: n = 31; adverse events: n = 16) discontinued anti-TNF-α agents. High baseline NLR was associated with an increased risk of anti-TNF-α agent withdrawal due to lack of efficacy (HR 2.12, p = 0.045). Our data suggest that baseline NLR and PLR are useful markers for predicting the treatment outcome of anti-TNF-α agents in RA patients.

Increased serum uric acid levels are associated with digital ulcers in patients with systemic sclerosis.

Endothelial injury/dysfunction is thought to be one of the earliest events in the development of vascular diseases in systemic sclerosis (SSc). Although hyperuricemia is also known to induce endothelial dysfunction and vascular inflammation, the effect of uric acid on the microvascular involvement in SSc has not been well established. We investigated whether increased serum uric acid (SUA) levels are associated with digital ulcers (DUs) in SSc. In this cross-sectional study, we consecutively recruited 71 women with SSc and 349 age- and sex-matched healthy subjects, and SUA levels were measured in all study subjects. SSc patients had significantly higher mean SUA levels than healthy subjects (4.5 ± 1 mg/dL vs 4.2 ± 0.9 mg/dL, p = 0.017), although a significantly lower body mass index (BMI) was observed in SSc patients than in controls. Among 71 SSc patients, 22 (31%) had DUs ever (active DUs, 8; healed DUs, 14). SSc patients presenting with DUs ever showed significantly higher SUA levels than those without this feature (median, 5.2 mg/dL vs 4.1 mg/dL, p = 0.009). In multivariable logistic regression models adjusted for confounders such as BMI and estimated glomerular filtration rate, increased SUA levels were associated with a significantly higher risk for the presence of DUs ever (OR 2.3, 95% CI 1.16-4.57, p = 0.018). Our data revealed that elevated SUA levels are independently associated with the presence of DUs in SSc patients, thereby suggesting the potential role of hyperuricemia in the pathogenesis of SSc vasculopathy.

Cognitive function of patients with rheumatoid arthritis is associated with disease activity but not carotid atherosclerotic changes.

OBJECTIVES: Although the relationship between atherosclerosis and cognitive impairment has been studied and replicated, whether cognitive deficits in RA can be attributed to atherosclerotic changes is not well understood. This study investigated cognitive function in patients with RA and evaluated whether cognitive function was affected by carotid arterial atherosclerosis. METHODS: We examined 70 RA patients and 40 healthy controls. RA activity was assessed by disease activity score with 28 joint-erythrocyte sedimentation rate (DAS28-ESR). Cognitive function was assessed by the Korean version of the Consortium to Establish a Registry for Alzheimer's disease (CERAD-K) neuropsychological battery. Carotid arteries were scanned for the presence of plaques and to assess intima-media thickness (IMT). We assessed potential risk factors of cognitive impairment in RA patients using regression analyses. RESULTS: There was a significant difference between RA patients and healthy controls in the verbal fluency (p=0.004) and Boston naming test (p=0.035). Carotid ultrasound revealed significantly more plaque in RA patients than in healthy controls (p=0.017). RA patients with memory impairment had significantly higher DAS28-ESR scores (p<0.001), age (p=0.009), and mean cIMT (p=0.027) than RA patients without memory impairment. In multivariable regression analysis, CERAD-K total score showed a significant negative correlation with age (ß=-0.415, p<0.001) or DAS28-ESR (ß=-4.685, p<0.001), but no correlation was found between CERAD-K total score and presence of plaque or cIMT. CONCLUSIONS: Our results indicate that disease activity of RA and aging contribute to cognitive dysfunction, but there was no association between cognitive function and carotid atherosclerotic changes in RA patients.

Baseline increased 18F-fluoride uptake lesions at vertebral corners on positron emission tomography predict new syndesmophyte development in ankylosing spondylitis: a 2-year longitudinal study.

The goal of this study was to demonstrate whether increased 18F-fluoride uptake lesions on positron emission tomography (PET) scan can predict new syndesmophyte development in patients with ankylosing spondylitis (AS). In 12 AS patients, 18F-fluoride PET and magnetic resonance imaging (MRI) was performed at baseline, and radiography was performed at baseline and the 2-year follow-up. The following data were recorded: the presence of increased 18F-fluoride uptake lesions on PET defined as an uptake greater than the uptake in the adjacent normal vertebral body; acute (type A) and advanced (type B) corner inflammatory lesions (CILs) and fat lesions on MRI; and syndesmophytes on radiography. Of 231 anterior vertebral corners without syndesmophyte at baseline, 13 type A CILs (5.5%), 2 type B CILs (0.9%), and 20 fat lesions (8.7%) on MRI and six increased fluoride uptake lesions (2.6%) on PET were observed. At the 2-year follow-up, 16 new syndesmophytes (6.9%) in eight AS patients (66.7%) occurred. New syndesmophytes developed significantly more frequently in anterior vertebral corners with increased 18F-fluoride uptake lesions (50%) or fat lesions (25%) at baseline than in those without such lesions (5.8 and 5.2%; p = 0.005 and p = 0.007, respectively). After adjusting confounding factors, baseline increased 18F-fluoride uptake lesions was independently associated with new syndesmophytes development (OR 13.8, 95% CI 1.5-124.3, p = 0.019). Fat lesions were also associated with new syndesmophytes formation. Our data suggest that 18F-fluoride PET may be applied to identify AS patients with high risk of future syndesmophyte formation.

Compliance and persistence with oral bisphosphonates for the treatment of osteoporosis in female patients with rheumatoid arthritis.

BACKGROUND: Poor adherence with oral bisphosphonates (BPs) can mitigate their therapeutic benefit for osteoporosis and is a significant clinical burden. Most previous studies regarding adherence with oral BPs have focused on postmenopausal osteoporosis, but little attention has been given to patients with rheumatoid arthritis (RA). Thus, we investigated compliance and persistence with oral BPs in the treatment of osteoporosis and analyzed risk factors for poor adherence in female patients with (RA) in real setting. METHODS: This is a retrospective longitudinal study including 396 female patients with RA in whom oral BPs were newly initiated from Aug 2004 to Aug 2014 at a university rheumatology center in South Korea. Compliance was quantified using the 1-year medication possession ratio (MPR), while persistence was defined as duration from the initiation to the end of BPs therapy without interruption exceeding 56 days. Seropositve RA was defined as having a positive test result for the presence of either rheumatoid factor or anti-cyclic citrullinated peptide antibody. RESULTS: Of 396 RA patients, 221 (55.8%) were prescribed risedronate 35 mg weekly; 17 (4.3%) received alendronate 70 mg weekly; and 158 (39.9%) received ibandronate 150 mg monthly. The 1-year MPR was 70.1% and the proportion of RA patients with the 1-year MPR ≥ 0.8 was 60.1%. A total of 274 (69.2%) patients discontinued oral BPs during the study period and persistence with BPs was 63.3% at 1 year, 50.7% at 2 years and 33.3% at 3 years. The most common cause of non-persistence was adverse events (47.5%), followed by poor health literacy (40.5%) and cost (12%). Both compliance and persistence with monthly oral BPs were significantly lower than those with weekly regimens (OR: 2.48, 95% CI: 1.59-3.89, P < 0.001 and HR: 2.19, 95% CI: 1.69-2.83, P < 0.001, respectively). Additionally, patients with seropositive RA showed better compliance and persistence with BPs compared with their seronegative counterparts. CONCLUSIONS: Compliance and persistence with oral BPs in RA patients were suboptimal in real practice, thereby limiting the efficacy of osteoporosis treatment. Extending the dosing interval of BPs may improve medication adherence in RA patients.

Structure-based design and biological evaluation of novel 2-(indol-2-yl) thiazole derivatives as xanthine oxidase inhibitors.

Inhibition of xanthine oxidase (XO) has obviously been a central concept for controlling hyperuricemia, which causes serious and painful inflammatory arthritis disease such as gout. We discovered a series of novel 2-(indol-2-yl)thiazole derivatives as XO inhibitors at the level of nanomolar activity. Structure-guided design using molecular modeling program (Accelrys Software program) provided an excellent basis for optimization of 2-(indol-2-yl)thiazole compounds. Structure-activity relationship indicated that hydrophobic alkoxy group (isopropoxy, cyclopentoxy) at 5-position and hydrogen binding acceptor (NO2, CN) at 7-position of indole ring appear as critical functional groups. Among the compounds, 2-(7-nitro-5-isopropoxy-indol-2-yl)-4-methylthiazole-5-carboxylic acid (9m) exhibits the most potent XO inhibitory activity (IC50 value: 5.1 nM) and the excellent uric acid lowering activity in potassium oxonate induced hyperuricemic rat model.

Insulin resistance is associated with digital ulcer in patients with systemic sclerosis.

OBJECTIVES: To investigate the relationship between insulin resistance and digital ulcers (DUs) in patients with systemic sclerosis (SSc). METHODS: Using a cross-sectional design, we recruited 73 consecutive female patients with SSc and 109 sex- and age-matched healthy controls in South Korea from July 2014 to June 2015. The magnitude of insulin resistance was measured using the homeostatic model assessment of insulin resistance (HOMA-IR). DUs ever included active and healed DUs and the extent of skin fibrosis was evaluated using the modified Rodnan skin score (MRSS). RESULTS: The HOMA-IR in patients with SSc was significantly higher than that in healthy controls (median 1.18 vs. 0.71, p<0.001). In SSc patients, 7 (9.6%) had active DUs and 14 subjects (19.2%) had healed DUs; thus, DUs ever were observed in 21 cases (28.8%). SSc patients with DUs ever had significantly higher HOMA-IR and MRSS compared with those without this feature (median, 2.05 vs. 0.99, p=0.001 and 14 vs. 9.5, p=0.011, respectively). After adjustment for confounding factors using multivariable logistic regression analyses, the HOMA-IR showed a significant positive association with the presence of DUs ever in patients with SSc (OR=1.43, 95% CI=1.01-2.05, p=0.048). In addition, higher MRSS was significantly correlated with DUs ever (OR=1.11, 95% CI=1.02-1.21, p=0.015). CONCLUSIONS: Insulin resistance was independently associated with the presence of DUs in patients with SSc and may be a potential biomarker for SSc micro-vasculopathy. Moreover, our data also suggest a potential contribution of insulin resistance to the pathogenesis of DUs.

Intravertebral vacuum cleft sign: a cause of vertebral cold defect on bone scan.

A 67-year-old female presented with an acute compression fracture with an intravertebral vacuum cleft (IVC) sign of the T12 vertebra. Her bone scan demonstrated a cold defect of the fractured vertebra. Although the IVC sign is related to vertebral osteonecrosis, to the best of our knowledge, a cold defect on a bone scan has not been reported in an acute compression fracture with an IVC sign. In this case review, various imaging findings of osteonecrotic compression fractures are discussed along with a review of the current literature.

Design and synthesis of novel 2-(indol-5-yl)thiazole derivatives as xanthine oxidase inhibitors.

Xanthine oxidase (XO) inhibitors have been widely used for the treatment of gout. Indole rings are frequently used as active scaffold in designing inhibitors for enzymes. Herein, we describe the structure-activity relationship for novel xanthine oxidase inhibitors based on indole scaffold. A series of novel tri-substituted 2-(indol-5-yl)thiazole derivatives were synthesized, and their in vitro inhibitory activities against xanthine oxidase and in vivo efficacy lowering uric acid level in blood were measured. Among them, 2-(3-cyano-2-isopropylindol-5-yl)-4-methylthiazole-5-carboxylic acid exhibits the most potent XO inhibitory activity (IC50 value: 3.5nM) and the excellent plasma uric acid lowering activity. Study of structure activity relationship indicated that hydrophobic moiety (e.g., isopropyl) at 1-position and electron withdrawing group (e.g., CN) at 3-position of indole ring and small hydrophobic group (CH3) at 4-position of the thiazole ring enhanced the XO inhibitory activity. Hydrophobic substitution such as isopropyl at 1-position of the indole moiety without any substitution at 2-position has an essential role for enhancing bioavailability and therefore for high in vivo efficacy.

Assessment of bone synthetic activity in inflammatory lesions and syndesmophytes in patients with ankylosing spondylitis: the potential role of 18F-fluoride positron emission tomography-magnetic resonance imaging.

OBJECTIVES: 18F-fluoride uptake represents active osteoblastic bone synthesis. We assessed bone synthetic activity in inflammatory lesions and syndesmophytes in patients with ankylosing spondylitis (AS) using 18F-fluoride positron emission tomography-magnetic resonance imaging (PET-MRI, Philips Healthcare, Cleveland, OH, USA) and x-ray. METHODS: All images of 12 AS patients were recorded with the presence or absence of increased 18F-fluoride uptake lesions on PET, acute (type A) or advanced (type B) corner inflammatory lesions (CILs) on MRI, syndesmophytes on x-ray at the anterior vertebral corners. An increased 18F-fluoride uptake lesion was defined as an uptake which is greater than the uptake in the adjacent normal vertebral body. The association of a CIL or syndesmophyte with an increased 18F-fluoride uptake lesion was investigated by generalised linear latent mixed models analysis to adjust within-patient dependence for total numbers of vertebral corners. RESULTS: There were 67 type A CILs (12.1%), 37 type B CILs (6.7%) and 58 increased 18F-fluoride uptake lesion (10.4%) out of 552 vertebral corners and there were 57 syndesmophytes (19.8%) out of 288 vertebral corners. A type A CIL (OR=3.2, 95% CI=1.6-6.5, p=0.001), type B CIL (OR=59.9, 95% CI=23.5-151.5, p<0.001) and syndesmpophyte (OR=21.8, 95% CI=5.5-85.2, p<0.001) were significantly associated with an increased 18F-fluoride uptake lesion. CONCLUSIONS: Our data suggest that an inflammatory lesion as well as a syndesmophyte is associated with active bone synthesis assessed by 18F-fluoride uptake in the spine of AS patients. 18F-fluoride PET-MRI may have the potential for investigating the pathogenesis of structural damage in AS.

Endoscopic cryotherapy for the treatment of epistaxis due to hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant vascular disease, involves mainly skin, mucocutaneous membranes, and viscera. Epistaxis is one of the most common symptoms of HHT, and chronic, frequently relapsing epistaxis can cause symptoms such as iron deficiency anemia, severe crusting, and nasal obstruction that can cause lower quality of life. Treatments for HHT range from medication and conservative management to more aggressive surgeries. None of the treatment options, however, have had satisfactory outcomes until now. We introduced cryotherapy for a patient with HHT and at least a 10-year history of frequent, severe epistaxis. This treatment strategy resulted in successful management of symptoms and no associated complications. We present herein a literature review and the clinical course and symptoms of an HHT patient who underwent cryotherapy.

Effect of abatacept versus conventional synthetic disease modifying anti-rheumatic drugs on rheumatoid arthritis-associated interstitial lung disease.

BACKGROUND/AIMS: To compare the effects of abatacept and conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) on the progression and development of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). METHODS: This multi-center retrospective study included RA patients receiving abatacept or csDMARDs who underwent at least two pulmonary function tests and/or chest high-resolution computed tomography (HRCT). We compared the following outcomes between the groups: progression of RA-ILD, development of new ILD in RA patients without ILD at baseline, 28-joint Disease Activity Score with the erythrocyte sedimentation rate (DAS28-ESR), and safety. Longitudinal changes were compared between the groups by using a generalized estimating equation. RESULTS: The study included 123 patients who were treated with abatacept (n = 59) or csDMARDs (n = 64). Nineteen (32.2%) and 38 (59.4%) patients treated with abatacept and csDMARDs, respectively, presented with RA-ILD at baseline. Newly developed ILD occurred in one patient receiving triple csDMARDs for 32 months. Among patients with RA-ILD at baseline, ILD progressed in 21.1% of cases treated with abatacept and 34.2% of cases treated with csDMARDs during a median 21-month follow-up. Longitudinal changes in forced vital capacity and diffusing capacity for carbon monoxide were comparable between the two groups. However, the abatacept group showed a more significant decrease in DAS28-ESR and glucocorticoid doses than csDMARDs group during the follow-up. The safety of both regimens was comparable. CONCLUSION: Abatacept and csDMARDs showed comparable effects on the development and stabilization of RA-ILD. Nevertheless, compared to csDMARDs, abatacept demonstrated a significant improvement in disease activity and led to reduced glucocorticoid use.

Blockade of CCL2/CCR2 signalling ameliorates diabetic nephropathy in db/db mice.

BACKGROUND: CCL2/C-C chemokine receptor 2 (CCR2) signalling is suggested to play a significant role in various kidney diseases including diabetic nephropathy. We investigated the renoprotective effect of a CCR2 antagonist, RS102895, on the development of diabetic nephropathy in a type 2 diabetic mouse model. METHODS: Six-week-old diabetic db/db and non-diabetic db/m mice were fed either normal chow or chow mixed with 2 mg/kg/day of RS102895 for 9 weeks. We investigated the effects of CCR2 antagonism on blood glucose, blood pressure, albuminuria and the structure and ultrastructure of the kidney. RESULTS: Diabetes-induced albuminuria was significantly improved after CCR2 antagonist treatment, and glucose intolerance was improved in the RS102895-treated diabetic mice. RS102895 did not affect blood pressure, body weight or kidney weight. Mesangial expansion, glomerular basement membrane thickening and increased desmin staining in the diabetic kidney were significantly improved after RS102895 treatment. The up-regulation of vascular endothelial growth factor mRNA expression and the down-regulation of nephrin mRNA expression were markedly improved in the kidneys of RS102895-treated diabetic mice. Increased renal CD68 and arginase II and urinary malondialdehyde in diabetes were effectively attenuated by RS102895 treatment. CONCLUSION: Blockade of CCL2/CCR2 signalling by RS102895 ameliorates diabetic nephropathy not only by improving blood glucose levels but also by preventing CCL2/CCR2 signalling from altering renal nephrin and VEGF expressions through blocking macrophage infiltration, inflammation and oxidative stress in type 2 diabetic mice.

Microvascular findings in patients with systemic lupus erythematosus assessed by fundus photography with fluorescein angiography.

OBJECTIVES: Although a series of trials support systemic lupus erythematosus (SLE) is associated with increased atherosclerosis and cardiovascular events, the link between microvascular structural change and the disease activity of SLE is not defined. We measured retinal microvasculature change by fundus photography with fluorescein angiography (FAG) and investigated the association between retinal vasculature and clinical parameters of SLE. METHODS: Fifty SLE patients and fifty healthy controls were included. Morphometric and quantitative features of the capillary image including retinal vascular sign and vessel diameters were measured with fundus photography and FAG. Information concerning SLE duration, cumulative dose of steroids and/or immunosuppressive drug intake was recorded, and autoantibodies were checked. SLE activity was assessed by SLE disease activity index (SLEDAI). RESULTS: The mean central retinal arteriolar equivalent (CRAE) was 89.7±14.5 µm in SLE patients, showing narrower arteriole than that of controls (102.2±11.3 µm). The mean central retinal venular equivalents (CRVE) was 127.7±14.8 µm in SLE patients, also, narrower than that of controls (144.1±14.2 µm), but both reached no statistical significance (p=0.154, p=0.609, respectively). Retinopathy was found in 26% of SLE patients. SLE patients with retinopathy were older than those without it, but reached no statistical significance. Disease duration, antidsDNA, and complement levels had no effect on the presence of retinopathy. SLE patients with retinopathy had a tendency to have higher cumulative steroid doses, hsCRP and IgG aCL levels than those without retinopathy. With multiple regression analysis, hsCRP and IgG aCL were identified as contributing factors to the decreased CRAE, whereas no contributing factor was found to CRVE. CONCLUSIONS: Retinopathy and retinal arteriolar narrowing were more common in SLE patients, and retinal arteriolar diameter had significant correlation with hsCRP and IgG aCL levels. Retinal imaging is a comparative method for the assessment of microvascular findings of SLE patients.

IL-32 aggravates synovial inflammation and bone destruction and increases synovial natural killer cells in experimental arthritis models.

This study was performed to investigate the effects of IL-32 on joint inflammation, bone destruction, and synovial cytokine expressions, and on synovial natural killer (NK) cell expressions in collagen-induced arthritis (CIA). CIA was induced by type II collagen in DBA1 mice, and phosphate-buffered saline (PBS group) or IL-32 (IL-32 group) were injected into both knee joints at day 28 and 32, then mice were killed at day 35. Severity of synovial inflammation and bone destruction was determined by histological scoring method, and synovial cytokine expressions such as IL-1ß, TNF-α, IL-17, IL-18, IFN-γ, IL-21, and IL-23 were measured by real-time RT-PCR and western blot. Synovial NK cell expressions were determined by real-time RT-PCR, western blot and immunohistochemistry, and chemokines and chemokine receptors expressions that are associated with NK cell migration were determined by real-time RT-PCR. Scores of synovial inflammation and bone destruction, synovial expressions of IL-1ß, TNF-α, IL-18, and IFN-γ were significantly increased in IL-32 group compared with PBS group. Synovial expressions of NK cell, and chemokines (CCL2 and CXCL9) and chemokine receptors (CCR2 and CCR5) that are associated with NK cell migration were significantly increased in IL-32 group compared with PBS group. IL-32 aggravated joint inflammation and bone destruction and increased synovial expressions of inflammatory cytokine and NK cells in CIA. These results suggest that IL-32 play a role in joint inflammation and bone destruction, and IL-32 might be a new target for treatment of rheumatoid arthritis.

Positive Effects of Biologics on Osteoporosis in Rheumatoid Arthritis.

Osteoporosis is a systemic skeletal disorder that causes vulnerability of bones to fracture owing to reduction in bone density and deterioration of the bone tissue microstructure. The prevalence of osteoporosis is higher in patients with autoimmune inflammatory rheumatic diseases, including rheumatoid arthritis (RA), than in those of the general population. In this autoimmune inflammatory rheumatic disease, in addition to known risk factors for osteoporosis, various factors such as chronic inflammation, autoantibodies, metabolic disorders, drugs, and decreased physical activity contribute to additional risk. In RA, disease-related inflammation plays an important role in local or systemic bone loss, and active treatment for inflammation can help prevent osteoporosis. In addition to conventional synthetic disease-modifying anti-rheumatic drugs that have been traditionally used for treatment of RA, biologic DMARDs and targeted synthetic DMARDs have been widely used. These agents can be employed more selectively and precisely based on disease pathogenesis. It has been reported that these drugs can inhibit bone loss by not only reducing inflammation in RA, but also by inhibiting bone resorption and promoting bone formation. In this review, the pathogenesis and research results of the increase in osteoporosis in RA are reviewed, and the effects of biological agents on osteoporosis are discussed.