Age-related low skeletal muscle mass correlates with joint space narrowing in knee osteoarthritis in a South Korean population: a cross-sectional, case-control study.

BACKGRUOUND: This study was conducted to analyze the effects of low skeletal muscle mass index (SMI) and obesity on aging-related osteoarthritis (OA) in the Korean population. METHODS: A total of 16,601 participants who underwent a dual-energy X-ray absorptiometry and 3,976 subjects with knee X-rays according to the modified Kellgren-Lawrence (KL) system were enrolled. Knees of ≥KL grade 2 were classified as radiologic OA. The severity of joint space narrowing (JSN) was classified by X-rays as normal, mild-to-moderate, and severe JSN in radiologic OA. The subjects were grouped as normal SMI (SMI of ≥-1 standard deviation [SD] of the mean), low SMI class I (SMI of ≥-2 SDs and <-1 SD), and low SMI class II (SMI of <-2 SDs). Obesity was defined as a body mass index (BMI) of ≥27.5 kg/m2. RESULTS: The modified KL grade and JSN severity were negatively correlated with the SMI and positively correlated with BMI and age. The SMI was negatively correlated with age. JSN severity was significantly associated with a low SMI class compared to a normal SMI, which was more prominent in low SMI class II than class I. Obesity was significantly associated with more severe JSN, only for obesity with a low SMI class. Furthermore, patients with a low SMI class, regardless of obesity, were prone to having more severe JSN. CONCLUSION: This study suggested that a low SMI class was associated with aging and that an age-related low SMI was more critically related to the severity of JSN in OA.

Idiopathic multicentric Castleman disease presenting progressive reticular honeycomb infiltration of lung and immunoglobulin G and immunoglobulin G4 dominant hypergammaglobulinemia: a case report.

Multicentric Castleman disease (MCD) is an uncommon systemic lymphoproliferative disorder that may cause multiple organ damage. Castleman disease-associated diffuse parenchymal lung disease (DPLD) has not been well studied. A 32-year-old man was referred to our hospital for progressive generalized weakness, light-headedness, and dyspnea on exertion for more than one year. Laboratory evaluations showed profound anemia, an elevated erythrocyte sedimentation rate, and an increased C-reactive protein level with polyclonal hypergammaglobulinemia. Chest radiography, computed tomography (CT), and positron emission tomography-CT scan demonstrated diffuse lung infiltration with multiple cystic lesions and multiple lymphadenopathy. In addition to these clinical laboratory findings, bone marrow, lung, and lymph node biopsies confirmed the diagnosis of idiopathic MCD (iMCD). Siltuximab, an interleukin-6 inhibitor, and glucocorticoid therapy were initiated. The patient has been tolerating the treatment well and had no disease progression or any complications in 4 years. Herein, we report this case of human herpesvirus-8-negative iMCD-associated DPLD accompanied by multiple cystic lesions, multiple lymphadenopathy, and polyclonal hypergammaglobulinemia with elevated immunoglobulin G (IgG) and IgG4 levels. We recommend a close evaluation of MCD in cases of DPLD with hypergammaglobulinemia.

Sulfatase 1 and sulfatase 2 as novel regulators of macrophage antigen presentation and phagocytosis.

BACKGRUOUND: Sulfation of heparan sulfate proteoglycans (HSPGs) is critical for the binding and signaling of ligands that mediate inflammation. Extracellular 6-O-endosulfatases regulate posttranslational sulfation levels and patterns of HSPGs. In this study, extracellular 6-O-endosulfatases, sulfatase (Sulf)-1 and Sulf-2, were evaluated for their expression and function in inflammatory cells and tissues. METHODS: Harvested human peripheral blood mononuclear cells were treated with phytohemagglutinin and lipopolysaccharide, and murine peritoneal macrophages were stimulated with interleukin (IL)-1ß for the evaluation of Sulf-1 and Sulf-2 expression. Sulf expression in inflammatory cells was examined in the human rheumatoid arthritis (RA) synovium by immunofluorescence staining. The antigen presentation and phagocytic activities of macrophages were compared according to the expression state of Sulfs. Sulfs-knockdown macrophages and Sulfs-overexpressing macrophages were generated using small interfering RNAs and pcDNA3.1 plasmids for Sulf-1 and Sulf-2, respectively. RESULTS: Lymphocytes and monocytes showed weak Sulf expression, which remained unaffected by IL-1ß. However, peritoneal macrophages showed increased expression of Sulfs upon stimulation with IL-1ß. In human RA synovium, two-colored double immunofluorescent staining of Sulfs and CD68 revealed active upregulation of Sulfs in macrophages of inflamed tissues, but not in lymphocytes of lymphoid follicles. Macrophages are professional antigen-presenting cells. The antigen presentation and phagocytic activities of macrophages were dependent on the level of Sulf expression, suppressed in Sulfs-knockdown macrophages, and enhanced in Sulfs-overexpressing macrophages. CONCLUSION: The results demonstrate that upregulation of Sulfs in macrophages occurs in response to inflammation, and Sulfs actively regulate the antigen presentation and phagocytic activities of macrophages as novel immune regulators.

Clinical impact of blood pressure variability in patients with COVID-19 and hypertension.

OBJECTIVE: This study aimed to investigate the relationship between blood pressure variability (BPV) and clinical outcomes in patients with coronavirus disease 2019 (COVID-19) and hypertension. METHODS: A total of 136 patients hospitalized with COVID-19 were enrolled in this study. Patients were grouped according to the presence of hypertension and BPV. Mean arterial pressure (MAP) measured at 8 a.m. and 8 p.m. was analyzed, and BPV was calculated as the coefficient of variation of MAP (MAPCV). High BPV was defined as MAPCV values above the median. We compared the age, level of C-reactive protein (CRP), creatine kinase-MB (CK-MB), N-terminal pro-B type natriuretic peptide (NT-proBNP), creatinine and in-hospital mortality and investigated the relationship among the groups. RESULTS: COVID-19 patients with hypertension were older (70 ± 12 vs. 53 ± 17 years; P < 0.001), had higher levels of CRP (9.4 ± 9.2 vs. 5.3 ± 8.2 mg/dL; P = 0.009), MAPCV (11.4 ± 4.8 vs. 8.9 ± 3.2; P = 0.002), and higher in-hospital mortality (19.6% vs. 5.9%; P = 0.013) than those without hypertension. There was a proportional relationship between BPV and age, levels of CRP, CK-MB, NT-proBNP, creatinine and in-hospital mortality (all, P < 0.05). In Cox regression analysis, advanced age [≥80 years, hazard ratio (HR) 10.4, 95% confidence interval (CI) 2.264-47.772, P = 0.003] and higher MAPCV (HR 1.617, 95% CI, 1.281-2.040, P < 0.001) were significantly associated with in-hospital mortality. CONCLUSION: High BPV in COVID-19 patients with hypertension is significantly associated with in-hospital mortality. Advanced age and systemic inflammation are proportional to high BPV. Additional attention is needed for COVID-19 patients with hypertension and high BPV.

An analysis of age-related loss of skeletal muscle mass and its significance on osteoarthritis in a Korean population.

BACKGROUND/AIMS: This study was conducted in order to analyze the effects of sarcopenia on age-related osteoarthritis (OA) of the knee in a Korean population. METHODS: All the Korean subjects who visited the Yeungnam University Medical Center Health Promotion Center between 2008 and 2012 in order to undergo a routine medical examination were enrolled. A total of 5,723 young, healthy people (2,959 males, 2,764 females) enrolled as normal subjects and 23,473 subjects (13,006 males and 10,467 females) were included for evaluation of the effects of sarcopenia on OA. There were 266 subjects who followed-up bioelectrical impedance analysis at a 4-year interval. Of 327 subjects enrolled in this study, knees with anteroposterior X-rays were assessed according to the Kellgren-Lawrence (K/L) grade. RESULTS: Skeletal muscle mass index (SMI) and basal metabolic rate (BMR) showed a steady decrease with the advance of age (p < 0.01), but SMI showed strong positive correlation with BMR (r = 0.72, ß = 30.96, p < 0.01). During the 4-year interval, BMR showed a significant decrease with aging (p < 0.01), consistently with the decrease of SMI. Knees with normal SMI were prone to be designated as K/L grade 0 or 1; however, subjects with sarcopenia showed a trend toward the higher K/L grade, classified as knee radiological osteoarthritis (ROA) (p < 0.01). CONCLUSIONS: The results of this study may indicate that sarcopenia as age-related loss of skeletal muscle mass is interactively correlated with the presence and severity of age-related OA.

Effects of Methotrexate on Carotid Intima-media Thickness in Patients with Rheumatoid Arthritis.

The purpose of this study was to evaluate the effects of rheumatoid arthritis (RA) and antirheumatic drugs on atherosclerosis by comparing carotid intima-media thickness (CIMT) as an indicator for cardiovascular diseases (CVD). This study included 44 female RA patients who met the 2010 ACR/EULAR criteria and age-matched 22 healthy females. CIMT was measured on both carotid arteries using a B-mode ultrasound scan. The mean value of both sides was taken as the CIMT of the subject. The CIMT was evaluated according to the use of drugs, disease activity and CVD risk factors in RA patients as a case-control study. Higher CIMT was observed in RA patients as compared with healthy subjects (0.705 ± 0.198 mm, 0.611 ± 0.093 mm, respectively, P < 0.05). With adjustment for the CVD risk factors, disease activity and the use of anti-rheumatic drugs, methotrexate (MTX) only showed a favorable effect on CIMT in RA. A significantly lower CIMT was observed in RA with MTX as compared with RA without MTX (0.644 ± 0.136 mm, 0.767 ± 0.233 mm, respectively, P < 0.05). The effects were correlated with MTX dosage (ß = -0.029, P < 0.01). The use of MTX should be considered in high priority not only to control arthritis but also to reduce the RA-related CVD risk to mortality.

Age-related NADPH Oxidase (arNOX) Activity Correlated with Cartilage Degradation and Bony Changes in Age-related Osteoarthritis.

The purpose of this study was to investigate the age-related NADPH oxidase (arNOX) activity in patients with age-related knee osteoarthritis (OA). Serum and cartilage arNOX activities were determined using an oxidized ferricytochrome C reduction assay. Full-thickness knee joint cartilages obtained through total knee replacement surgery were graded according to the Outerbridge (OB) classification. Radiographic severity of OA was determined on Knee X-rays according to the Kellgren-Lawrence (K/L) grading system. Cartilage ß-galactosidase, HIF-1α, and GLUT-1 expression levels were evaluated as markers for tissue senescence, hypoxia, and glycolysis. Higher arNOX activities occurred with higher levels of cartilage ß-galactosidase, HIF-1α, and GLUT-1 (P = 0.002). arNOX activity in cartilages with surface defects (OB grade II, III) was higher than in those without the defects (OB grade 0, I) (P = 0.012). Cartilage arNOX activity showed a positive correlation with serum arNOX activity (r = -0.577, P = 0.023). Serum arNOX activity was significantly higher in the OA subgroup with bilateral ROA than in the OA with no or unilateral ROA (2.449 ± 0.81, 2.022 ± 0.251 nM/mL, respectively, P = 0.019). The results of this study demonstrate that OA itself is not a cause to increase arNOX activities, however, arNOX hyperactivity is related to a high degree of cartilage degradation, and a high grade and extent of ROA in age-related OA.

(18F)Fluoro-deoxy-D-glucose uptake of knee joints in the aspect of age-related osteoarthritis: a case-control study.

BACKGROUND: This study investigated (18)F-fluorodeoxyglucose ((18)F-FDG) uptake at knee joints for determination of metabolic alteration in association with the advance of age and joint degeneration such as osteoarthritis (OA). METHODS: A total of 166 knees from 83 healthy persons who presented for routine health examination and positron emission tomography-computed tomography (PET/CT) were enrolled in this study. History of knee OA and joint symptoms and signs were reviewed. The maximum standardized uptake values (SUVmax) of cartilage and mean SUV (SUVmean) between the epiphyseal plates of femur and tibia were evaluated at knee joints. Assessment of radiological bony changes was performed using the Kallgren-Lawrence (K/L) grading system with reconstructed CT images of the knee. The joint symptoms and signs were counted and used for diagnosis of clinical and radiological OA of the knee. RESULTS: The SUVmean of the knee joints showed a remarkable increase with aging in females (r = 0.503, p < 0.01). Remarkable changes of SUVmean were observed with history of OA (p < 0.01). The SUVmean of joint and the intra-articular SUVmax showed higher values in clinical and radiological OA than in normal joints (p < 0.01). Joint-SUVmean showed significant correlation with OA severity graded according to K/L score (p < 0.05). The intra-articular SUVmax showed a significant increase in symptomatic joints, indicating OA in correlation with the joint-SUVmean (p = 0.01). CONCLUSIONS: The increasing (18)F-FDG uptakes of knee joints showed agreement with aging in females and clinical and radiological knee OA, indicating that the metabolic alterations were consistent with diagnosis and demographic aspect of OA as a surrogate marker for degeneration of the knee in association with aging.

Effects of hypoxia/ischemia on catabolic mediators of cartilage in a human chondrocyte, SW1353.

Cells from a human chondrocyte cell line were studied in 1% oxygen and/or a lower glucose concentration (5.5 mM), compared to the routine culture conditions of normoxia and high glucose. HIF-1α, IL-1ß, IL-6, IL-8, COX-2, TNFα, LIF, MMP-3, MMP-13, and reactive oxygen species (ROS) were evaluated, respectively. Effects of hypoxia inducing expression of HIF-1α were statistically significant at 72 h (p<0.05). Increased production of ROS by hypoxia was also observed with passage of time (p<0.05). The effects of hypoxia on HIF-1α and IL-1ß were potentiated by 5.5 mM glucose, especially after 48 h (p<0.05). IL-8 production was significantly induced in 1% O(2), with 5.5 mM glucose (p<0.01). IL-8 mRNA expression and production in response to IL-1ß were potentiated by hypoxia/ischemia (p<0.05, p<0.01, respectively). Up-regulation of IL-1ß, ROS, and IL-8 by hypoxia/ischemia in human chondrocytes may occur in correlation with HIF-1α. IL-8 response to IL-1ß may be potentiated synergically by hypoxia/ischemia, as an effector of hypoxia/ischemia. The results may suggest aggressive biology of the ordinary cartilage hypoxia/ischemia in the context of arthro-degeneration.

Three cases of fever of unknown origin (FUO) with acute multifocal non-bacterial osteitis (NBO) as reactive osteomyelitis.

Evaluation for fever of unknown origin (FUO) requires a long list of studies. Recently, the validity of PET scan in FUO evaluation has been approved for screening and qualification. Non-bacterial osteitis (NBO) refers to non-bacterial and non-specific inflammation of bone, which is usually chronic, and involves multiple bony sites. We have experienced 3 cases of FUO associated with increased symmetric multiple fluorodeoxyglucose uptake preferentially at the epiphysis of the femur and tibia on fusion Positron emission tomography/Computed tomography (PET/CT). Patients were young women, who complained of intermittent fever lasting several months, which was associated only with neutropenia and relative lymphocytosis. Bone biopsies revealed increased lymphocytes and histiocyte infiltration of the cortical bone with reactive bone marrow. With no evidence of infection, the fever showed spontaneous remission within 2 weeks of conservative treatment. We report on 3 cases of FUO with self-limited acute NBO as reactive osteomyelitis and suggest that this unique pattern on PET/CT would be helpful for FUO evaluation.

A case of minimal change disease treated successfully with mycophenolate mofetil in a patient with systemic lupus erythematosus.

The World Health Organization classifies lupus nephritis as class I to V or VI. However, a few cases of minimal change glomerulopathy have been reported in association with systemic lupus erythematosus (SLE). Mycophenolate mofetil has been shown to be effective for treatment of minimal change disease and lupus nephritis. A 24-year-old woman diagnosed with SLE five years prior to presentation complained of a mild generalized edema. The urinalysis showed microscopic hematuria and proteinuria. The assessed amount of total proteinuria was 1,618 mg/24 hours. A renal biopsy demonstrated diffuse fusion of the foot processes of podocytes on electron microscopy. Mycophenolate mofetil was started in addition to the maintenance medications of prednisolone 10 mg/day and hydroxychloroquine 400 mg/day. After six months of treatment, the microscopic hematuria and proteinuria resolved, and the total urine protein decreased to 100 mg/24 hours.

Renal cell carcinoma presenting as Henoch-Schönlein purpura with leukocytoclastic vasculitis, hematuria, proteinuria and abdominal pain.

Some infectious, rheumatic, allergic diseases, and malignancies have been associated with leucocytoclastic vasculitis (LCV). LCV and cancer occur most frequently in patients with hematological malignancies such as lymphomas and leukemias. There have been a few prior cases reported of LCV associated with renal cell carcinoma (RCC). A 25-year-old male patient was referred from the department of dermatology and nephrology because of recurrent petechiae on both lower legs for several months; the patient also had a tumor of the left kidney. The findings on the skin biopsy were compatible with the diagnosis of LCV. The patient was diagnosed as having Henoch-Schönlein purpura (HSP) with LCV. A CT scan performed due to abdominal pain revealed a mass on the upper pole of the left kidney. A partial nephrectomy of the left kidney including the tumor was performed. The pathology report was consistent with a clear cell type of renal cell carcinoma, Fuhrman's grade 2; the tumor measured 0.9 x 0.8 cm and focal segmental glomerulosclerosis was noted in non-neoplastic regions. Here, we report a case of LCV associated with RCC presenting as HSP. This case illustrates the importance of evaluating patients for an underlying malignancy when HSP or LCV is diagnosed.

Autoimmune lymphoproliferative syndrome-like syndrome presented as lupus-like syndrome with mycobacterial joint infection evolved into the lymphoma.

The autoimmune lymphoproliferative syndrome (ALPS) and ALPS-like syndrome are variable clinical conditions characterized by lymphoproliferative disease, autoimmune cytopenias and susceptibility to malignancy. A 59-year-old woman was admitted to the hospital for intractable generalized pain and stiffness with multiple swollen joints for 2 weeks. A low-grade fever, intermittent hypotension and confusion were associated with the pain. The evaluation revealed multiple joint bony erosions with effusion and a ruptured Baker's cyst and positive AFB testing on the joint biopsy of the right wrist. In addition, there were a macular skin rash with telangiectasia and perivascular lymphocyte infiltration, a cytopenia without abnormal cells, a hepatosplenomegaly, a pericardial thickness with effusion and pleural effusion. The patient was treated with anti-mycobacterial drugs, NSAIDs and glucocorticoids for 10 months. But with the symptoms worsening, the patient developed cervical lymph node enlargements and was diagnosed as a diffuse large B cell lymphoma with hemophagocytosis on biopsy.

A case of adult onset Still's disease with systemic inflammatory response syndrome complicated by fatal status epilepticus.

Prolonged spiking fever, an evanescent salmon-colored rash, arthralgia or arthritis, leukocytosis and organ dysfunction are characteristic of adult onset Still's disease (AOSD). A 25-year-old woman with fever lasting over 3 weeks presented to our clinic. The patient had a spiking fever, sore throat, tender lymph nodes, a fine pink-colored skin rash, arthralgia, myalgia with a high ESR, ferritin and elevated hepatic enzymes. NSAID and prednisolone were prescribed for AOSD with SIRS. After 4 days of therapy, with mild confusion, the patient went into status epilepticus lasting several hours and died after cardiovascular collapse. There has been only one case of status epilepticus associated with AOSD in the medical literature. Here we report a case of AOSD with SIRS complicated by fatal status epilepticus.

A 2-week, multicenter, randomized, double-blind, double-dummy, add-on study of the effects of titration on tolerability of tramadol/acetaminophen combination tablet in Korean adults with knee osteoarthritis pain.

BACKGROUND: Combined tramadol/acetaminophen is used to treat pain related to osteoarthritis. However, adverse events (AEs) leading to discontinuation can occur. Dose titration may decrease the risk for AEs. OBJECTIVE: The aim of this study was to assess the effect of tramadol/acetaminophen titration on the development of AEs leading to treatment discontinuation in patients with knee osteoarthritis. METHODS: This 2-week, multicenter, randomized, double-blind, double-dummy, add-on study was conducted at 12 tertiary referral university hospitals in the Republic of Korea. Patients aged 35 to 75 years with knee osteoarthritis receiving a stable dose of NSAIDs and with a daily mean pain-intensity score of > or = 4 on a numeric rating scale (NRS) (0 = no pain to 10 = worst pain) during the 48 hours prior to enrollment were eligible. Patients were randomly assigned to receive 1 tablet of tramadol/acetaminophen 37.5/325 mg QD and 1 placebo BID for 3 days, followed by 1 active tablet BID and 1 placebo QD for 4 days, followed by 1 active tablet TID for 7 days (titration group) or 1 tablet of combined tramadol 37.5 mg/acetaminophen 325 mg TID for 14 days (nontitration group). The primary outcome measure was the rate of treatment discontinuation due to AEs. Secondary outcome measures were time to discontinuation due to AEs, prevalences and characteristics of AEs, decrease from baseline in pain intensity as measured on the NRS, and change in the Korean version of the Western Ontario and McMaster Universities (K-WOMAC) index score (scale: 0 = best to 100 = worst). RESULTS: A total of 250 patients were enrolled (92.0% female; mean [SD] age, 60.2 [7.8] years; mean [SD] weight, 60.0 [9.2] kg [range, 37.5-90.7 kg]; all Korean). The discontinuation rate was significantly lower in the titration group than in the nontitration group (10.5% vs 26.2%; P < 0.001). The Kaplan-Meier survival curve showed that the rates of discontinuation due to AEs were similar in the 2 groups up to day 2, but thereafter the discontinuation rate was significantly lower in the titration group. The most common AEs were nausea (12.1% and 24.6% in the titration and nontitration groups, respectively; P = 0.008), vomiting (4.0% and 17.2%; P < 0.001), and dizziness (9.7% and 22.1%; P = 0.005). No serious AEs were reported in either group. Tramadol/acetaminophen use was associated with a similar decrease from baseline in pain in both the titration and nontitration groups (mean [SD] Delta: NRS, -1.60 [1.62] vs -1.68 [1.58]; total K-WOMAC, -12.86 [13.73] vs -12.52 [16.58]). CONCLUSIONS: In this population of Korean patients with knee osteoarthritis pain managed with a stable dose of NSAIDs, titration of tramadol/acetaminophen over 12 days was associated with improved tolerability and a significantly lower discontinuation rate compared with nontitration. Both regimens significantly reduced from baseline associated with osteoarthritis.