Mortality factors in idiopathic inflammatory myopathy: focusing on malignancy and interstitial lung disease.

OBJECTIVES: The objective of this study was to assess the incidence and common types of concomitant malignancies and to define predictive factors of death in Korean patients with idiopathic inflammatory myopathy (IIM). METHODS: From January 1989 to May 2011, 162 patients were diagnosed with IIM at a university hospital in Korea. The medical records were retrospectively reviewed. The clinical findings of the patients were compared for malignancy, and the prognostic factors predicting death were analyzed. RESULTS: Malignancies were found in 17 patients (10.5 %), all of whom had a significantly lower frequency of interstitial lung disease (ILD) and an older age at onset. The main causes of death were ILD and malignancy. Older age at diagnosis, presence of malignancy, rapidly progressive ILD and minimal creatinine phosphokinase (CPK) elevation were independent risk factors for death. CONCLUSIONS: Malignancy was one of the most serious risk factor for death in our patients with IIM. Early discovery of malignancy is important, and an extensive investigation for common malignancies in each region should be done at diagnosis and for a minimum of 2 years thereafter. As minimally elevated CPK levels in ILD patients may be associated with fatal ILD, an early evaluation and a more aggressive treatment of ILD should be considered in these patients.

Upregulation of interleukin-1ß production by 1,25-dihydroxyvitamin D(3) in activated human macrophages.

1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) plays important roles in the immune system. In contrast to its well known function in the adaptive immune system, much less is known about the immunoregulatory effects of 1,25(OH)(2)D(3) in the innate immune system, especially on activated human macrophages. Here we found that 1,25(OH)(2)D(3) strongly stimulated the production of interleukin-1ß (IL-1ß) in PMA-differentiated U937 cells and human monocyte-derived macrophages treated with lipopolysaccharide (LPS) or PMA. In this study, Erk1/2 appeared to mediate 1,25(OH)(2)D(3)-induced expression of IL-1ß. Parallel to the increased production of IL-1ß, 1,25(OH)(2)D(3) increased the expression and phosphorylation of the CCAAT enhancer-binding protein ß (C/EBPß), which is one of the key transcriptional regulatory factors for IL-1ß transcription. These results suggest that 1,25(OH)(2)D(3) may function as a proinflammatory molecule in inflammatory macrophages.

Direct inhibition of human RANK+ osteoclast precursors identifies a homeostatic function of IL-1beta.

IL-1ß is a key mediator of bone resorption in inflammatory settings, such as rheumatoid arthritis (RA). IL-1ß promotes osteoclastogenesis by inducing RANKL expression on stromal cells and synergizing with RANKL to promote later stages of osteoclast differentiation. Because IL-1Rs share a cytosolic Toll-IL-1R domain and common intracellular signaling molecules with TLRs that can directly inhibit early steps of human osteoclast differentiation, we tested whether IL-1ß also has suppressive properties on osteoclastogenesis in primary human peripheral blood monocytes and RA synovial macrophages. Early addition of IL-1ß, prior to or together with RANKL, strongly inhibited human osteoclastogenesis as assessed by generation of TRAP(+) multinucleated cells. IL-1ß acted directly on human osteoclast precursors (OCPs) to strongly suppress expression of RANK, of the costimulatory triggering receptor expressed on myeloid cells 2 receptor, and of the B cell linker adaptor important for transmitting RANK-induced signals. Thus, IL-1ß rendered early-stage human OCPs refractory to RANK stimulation. Similar inhibitory effects of IL-1ß were observed using RA synovial macrophages. One mechanism of RANK inhibition was IL-1ß-induced proteolytic shedding of the M-CSF receptor c-Fms that is required for RANK expression. These results identify a homeostatic function of IL-1ß in suppressing early OCPs that contrasts with its well-established role in promoting later stages of osteoclast differentiation. Thus, the rate of IL-1-driven bone destruction in inflammatory diseases, such as RA, can be restrained by its direct inhibitory effects on early OCPs to limit the extent of inflammatory osteolysis.

Diagnosis of Paget's disease of the pelvis using F-18 FDG PET/CT.

Sclerotic lesions of the right iliac bone were discovered incidentally in a 52-year-old Korean woman. In this case, imaging of the right iliac bone showed intense osteoblastic activity on the bone scan and very mild F-18-fluoro-2-deoxyglucose (FDG) uptake on positron emission tomography (PET). Since Paget's disease is rare in Koreans, we aimed to rule out other bone diseases such as osteoblastic metastasis or osteomyelitis. These results allowed us to exclude chronic osteomyelitis or malignancy and clarify the diagnosis of Paget's disease of the iliac bone. This case illustrates how F-18 FDG PET/CT can be a useful tool in the differential diagnosis of various bone diseases.

Functional monocyte chemoattractant protein-1 promoter -2518 polymorphism and systemic lupus erythematosus: a meta-analysis.

The monocyte chemoattractant protein-1 (MCP-1) promoter -2518 A/G polymorphism has been reported inconsistently to be associated with systemic lupus erythematosus (SLE) and lupus nephritis (LN). The aim of this study was to explore whether the MCP-1 polymorphism confers susceptibility to SLE or LN. We surveyed studies on the MCP-1 polymorphism and SLE or LN identified by MEDLINE or manual searches. Meta-analysis was conducted on the AA genotype (recessive effect), AA, and AG genotypes (dominant effect), AA versus GG (genotype contrast), and on the A allele of MCP-1 in SLE and LN in each ethnic population studied and on all subjects. Ten studies, which included 1,739 SLE patients and 1,680 controls, were included in our meta-analysis. These consisted of two European, six Asian, one Latin American, and one mixed study. We did not find any association between the MCP-1 -2518 A/G polymorphism and SLE in all subjects or in ethnic groups. Meta-analysis also failed to reveal an association between the MCP-1 -2518 A/G polymorphisms and LN. This meta-analysis on 3419 subjects indicates that no association exists between the MCP-1 -2518 A/G polymorphism and SLE or LN.

Fc receptor-like 3 -169 C/T polymorphism and RA susceptibility: a meta-analysis.

The Fc receptor-like 3 (FCRL3) -169 C/T polymorphism has been reported to be associated with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), but with inconsistent results. The aim of this study was to explore whether the FCRL3 -169 C/T polymorphism confers susceptibility to RA and SLE. The authors conducted a random effect meta-analysis on the associations between the C/C (recessive effect) or C/C + C/T (dominant effect) genotype or the allele C of the FCRL3 -169 polymorphisms and RA or SLE in different populations. In total, 15 separate comparisons, 12 for RA and 3 for SLE, drawn from nine European and six Asian population samples were included in this meta-analysis. No association between RA and the FCRL3 C allele was found for all study subjects (OR = 1.064, 95% CI = 0.987-1.146, p = 0.107). However, stratification by ethnicity indicated that the FCRL3 C allele was significantly associated with RA in Asians (OR = 1.203, 95% CI = 1.097-31.319, p < 0.001). Conversely, no association was detected for this allele and RA in Europeans (OR = 0.997, 95% CI = 0.931-1.068, p = 0.933). The ORs for the C/C + C/T and C/C genotypes in these ethnic groups showed the same trends as the FCRL3 C allele. An association between SLE and the FCRL3 -169 A allele was found in all study subjects (OR = 1.115, 95% CI = 1.003-1.240, p = 0.043), but meta-analysis excluding studies with controls not in HWE did not show the association. This meta-analysis suggests that the FCRL3 -169 C/T polymorphism is a significant risk factor for RA in Asians, but not in Europeans.

Association between the rs7574865 polymorphism of STAT4 and rheumatoid arthritis: a meta-analysis.

The aim of this study was to determine whether the rs7574865 polymorphism of STAT4 (signal transducers and activators of transcription 4) confers susceptibility to rheumatoid arthritis (RA) in populations with different ethnicities. A meta-analysis was conducted on the T allele of the STAT4 rs7574865 polymorphism in 15 studies containing 16,088 RA patients and 16,509 normal control subjects. Meta-analysis revealed an association between RA and the STAT4 rs7574865 T allele in all subjects (OR = 1.271, 95% CI = 1.197-1.350, P < 0.001). Furthermore, the STAT4 rs7574865 T allele was found to be significantly associated with RA in Europeans and Asians (OR = 1.300, 95% CI = 1.195-1.414, P < 0.001; OR = 1.216, 95% CI = 1.135-1.303, P < 0.001). Stratification of RA patients according to the presence of anti-CCP antibody revealed a statistically significant association between the T allele and RA in both anti-CCP-positive and -negative RA patients versus controls. Europeans had the lowest (21.4%) and Asians had the highest (32.0%) prevalence of the T allele among the populations studied. In conclusion, this meta-analysis confirms that the STAT4 rs7574865 polymorphism is associated with RA susceptibility in different ethnic groups, and that its prevalence is ethnicity dependent.

Associations between osteoprotegerin polymorphisms and bone mineral density: a meta-analysis.

Associations between polymorphisms of the osteoprotegerin gene (OPG) and bone mineral density (BMD) have been studied by several research groups, but results are mixed. Accordingly, the authors performed a meta-analysis on studies of associations between OPG polymorphisms and BMD. Appropriate studies were identified using MEDLINE and by manual searching. A total of eight separate comparisons were considered in this meta-analysis. Individuals with the GG genotype of G1181C were found to have a significantly lower mean lumbar BMD than subjects with the CC genotype (WMDs -0.051 g/cm(2), 95% confidence interval -0.079--0.023, P < 0.001), and similar results were obtained in European and Asian populations. In contrast to G1181C, no association was found between the A163G and T950C polymorphisms and lumbar BMD. In terms of femoral neck BMD, the GG genotype of G1181C was associated with a significantly lower BMD than the CC genotype in Europeans but not in Asians. Total hip BMD was lower for the GG genotype of G1181C than for the CC or GC genotypes in Europeans. A difference in total hip BMD was found between the AG and GG genotypes of the A163G polymorphism by meta-analyses in Europeans, but no differences were found between the genotypes of the T950C polymorphism and total hip BMD in Europeans. Summarizing, the present study demonstrates that the OPG G1181C polymorphism is associated with lumbar BMD in Europeans and Asians, and with femoral neck and total hip BMD in Europeans only.

Effect of glucosamine or chondroitin sulfate on the osteoarthritis progression: a meta-analysis.

The aim of this study was to assess the structural efficacies of daily glucosamine sulfate and chondroitin sulfate in patients with knee osteoarthritis (OA). The authors surveyed randomized controlled studies that examined the effects of long-term daily glucosamine sulfate and chondroitin sulfate on joint space narrowing (JSN) in knee OA patients using the Medline and the Cochrane Controlled Trials Register, and by performing manual searches. Meta-analysis was performed using a fixed effect model because no between-study heterogeneity was evident. Six studies involving 1,502 cases were included in this meta-analysis, which consisted of two studies on glucosamine sulfate and four studies on chondroitin sulfate. Glucosamine sulfate did not show a significant effect versus controls on minimum JSN over the first year of treatment (SMD 0.078, 95% CI -0.116 to -0.273, P = 0.429). However, after 3 years of treatment, glucosamine sulfate revealed a small to moderate protective effect on minimum JSN (SMD 0.432, 95% CI 0.235-0.628, P < 0.001). The same was observed for chondroitin sulfate, which had a small but significant protective effect on minimum JSN after 2 years (SMD 0.261, 95% CI 0.131-0.392, P < 0.001). This meta-analysis of available data shows that glucosamine and chondroitin sulfate may delay radiological progression of OA of the knee after daily administration for over 2 or 3 years.

Association of STAT4 polymorphism with rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis.

STAT4 is a transcription factor that has been implicated in the pathogenesis of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Recently, several reports has documented that a STAT4 haplotype is associated with RA, SLE and Sjogren's syndrome. To summarize and review these findings, we conducted a meta-analysis of all relevant reports published before September 2008. Studies on STAT4 rs7574865 single nucleotide polymorphism (SNP) of RA and SLE were identified using PubMed. Meta-analyses were performed for 15,609 patients with RA and 15,793 controls from 14 published studies and for 2,478 patients with SLE and 5,058 controls from 8 published studies. Meta-odds ratios (ORs) and 95% confidence intervals (CIs) based on random effects models were calculated for all available studies. The overall ORs for the minor T allele of STAT4 rs7574865 SNP were 1.27 (95% CI 1.20-1.34) in RA and 1.57 (95% CI 1.44-1.71) in SLE. Asian controls have significantly higher allele frequency (32%) for the minor T allele of STAT4 rs7574865 SNP than population of European origin (22%), however, there was no significant difference of ORs for RA and SLE by ethnicity. No apparent effect of anti-CCP positivity was found in stratified analysis. The risk of STAT4 genotype for SLE was significantly higher than for RA in populations of European origin and Asian. The results of our meta-analysis demonstrated that STAT4 rs7574865 SNP is significantly associated with RA and SLE. In addition to specific alleles of HLA-DRB1, the minor T allele of STAT4 rs7574865 SNP is a common RA risk factor in populations of European origin and Asian.

A new onset of systemic lupus erythematosus developed after bee venom therapy.

Lupus is a systemic autoimmune disease of an unknown origin, and systemic lupus erythematosus (SLE) can be triggered by numerous stimuli. Bee venom therapy is an alternative therapy that is believed to be effective for various kinds of arthritis. We present here a case of a 49-year-old female who experienced a new onset lupus after undergoing bee venom therapy, and this looked like a case of angioedema. The patient was successfully treated with high dose steroids and antimalarial drugs. We discuss the possibility of bee venom contributing to the development of SLE, and we suggest that such treatment should be avoided in patients with lupus.

Advanced glycation end-products (AGEs): a novel therapeutic target for osteoporosis in patients with rheumatoid arthritis.

Bone losses in patients with rheumatoid arthritis (RA) include focal marginal joint erosion, juxtaarticular osteopenia, and systemic osteoporosis. Systemic osteoporosis prevalent in RA is associated with increased fracture rates and is a cause of very high morbidity and mortality. A couple of reports showed that advanced glycation end-products (AGEs) influence osteoclasts (bone resorption) and osteoblasts (bone formation), so AGEs may be have an important role in the pathogenesis of osteoporotic bone diseases. Recently, it was demonstrated that AGEs is increased in patients with RA and the concentration of AGEs correlates with the disease activity of RA. We present a hypothesis that AGEs may be involved in the pathogenesis of osteoporosis in patients with RA and the AGE crosslink breaker alagebrium will be a powerful therapeutic agent for osteoporosis in patients with RA.

Association between the A1330V polymorphism of the low-density lipoprotein receptor-related protein 5 gene and bone mineral density: a meta-analysis.

The association between the A1330V polymorphism of the low-density lipoprotein receptor-related protein 5 gene (LRP5) with bone mineral density (BMD) has been studied, but results have been mixed. Accordingly, the authors performed a meta-analysis on studies on the association between the A1330V LRP5 polymorphism and BMD. Appropriate studies were identified using MEDLINE and by manual searching. A total of 7 separate comparisons were considered in this meta-analysis. Individuals with the AA genotype showed significantly higher lumbar BMD than those with the AV/VV or VV genotype. Weighted mean differences (WMDs) were 0.147 g/cm(2) (95% confidence interval [CI] 0.069-0.224, P < 0.001) and 0.182 g/cm(2) (95% CI 0.024-0.340, P = 0.024) without between-study heterogeneity for AA versus AV/VV and AA versus VV, respectively. Six studies analyzed femur neck (FN) BMD. Individuals with the AA genotype had a significantly higher FN BMD than those with the AV/VV genotype (WMD = 0.165 g/cm(2), 95% CI = 0.087-0.215, P < 0.001), without between-study heterogeneity. Trochanter BMD was measured in three studies. Results showed that subjects with the AA genotype tended to have higher BMD than patients with the AV or VV genotype (WMD = 0.136 g/cm(2), 95% CI = -0.002 to 0.274, P = 0.053). In conclusion, this meta-analysis shows that the LRP5 A1330V polymorphism is associated with BMD, and that individuals with the AA genotype have a higher BMD than those with the AV/VV or VV genotype.

Association of Fcgamma receptor polymorphisms with adult onset Still's disease in Korea.

OBJECTIVE: Fcgamma receptors (FcgammaR) have important functions in the regulation of immune response and clearance of immune complex. High levels of immunoglobulins have been observed in patients with the active stage of adult onset Still's disease (AOSD), and high-dose intravenous immunoglobulin treatment has decreased the disease activity of AOSD. We investigated polymorphisms of FcgammaR as genetic factors influencing susceptibility or disease course of AOSD in Korea. METHODS: We genotyped the FcgammaRIIA H/R131, IIIA F/V176, and IIIB NA1/NA2 loci in 98 patients with AOSD and 151 healthy controls. Genotyping was performed using sequence-specific PCR. Patients with AOSD were subdivided into groups according to disease course: monocyclic systemic, polycyclic systemic, or chronic articular type. Allelic, genotypic, and haplotypic associations were analyzed by chi-square test. RESULTS: No significant skewing in any of the 3 FcgammaR polymorphisms was found between Korean AOSD patients and controls. FcgammaRIIA R/R131 and R/H131 genotype in patients with chronic articular-type disease was more frequent than in controls (p = 0.006 and p(corr) = 0.018). No differences of genotypic and allelic frequencies were found between other disease course types and controls. Haplotype IIA R131-IIIA F176-IIIB NA2 was more frequent in AOSD patients than in controls (p = 0.021). CONCLUSION: Although FcgammaR polymorphisms are not associated with development of AOSD in Koreans, the haplotype IIA R131-IIIA F176-IIIB NA2 may be associated with AOSD. Also, the FcgammaRIIA polymorphism may be associated with chronic articular-type AOSD. We need to identify whether these polymorphisms are associated with a response to anti-tumor necrosis factor agents in patients with AOSD.

Vitamin D receptor TaqI, BsmI and ApaI polymorphisms and osteoarthritis susceptibility: a meta-analysis.

OBJECTIVE: Genetic factors may play a role in the development of osteoarthritis (OA), and vitamin D receptor (VDR) polymorphisms have been associated with several common diseases including OA by some studies. The aim of this study was to explore whether the VDR polymorphisms confer susceptibility to OA. METHODS: We conducted meta-analyses on the associations between the VDR TaqI, BsmI, ApaI polymorphisms and OA using: (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) contrast of homozygotes, using fixed and random effects models. RESULTS: A total of 10 relevant studies on VDR polymorphisms and OA were included in this meta-analysis, which involved in total 1591 OA patients and 1781 controls. Nine studies were performed on VDR TaqI polymorphisms, 6 on VDR BsmI polymorphisms, 5 on VDR ApaI polymorphisms. Accordingly, to our meta-analysis of VDR TaqI polymorphisms, no association was found between OA and the VDR TaqI T allele among in all study subjects (OR=0.841, 95% CI=0.663-1.067, p=0.155). Stratification by ethnicity yielded no association between the VDR TaqI T allele and OA in Europeans or Asians. Moreover, no association was found between OA and the VDR TaqI polymorphisms by the meta-analyses of recessive and dominant models, and contrast of homozygotes. No association was found between OA and the VDR polymorphisms with respect to the BsmI and ApaI polymorphisms by meta-analyses. CONCLUSIONS: No association was found between the VDR TaqI, BsmI, or ApaI polymorphisms and OA susceptibility by this meta-analysis, which included 3372 subjects.

A Case of Obstructive Jaundice Caused by Paradoxical Reaction during Antituberculous Chemotherapy for Abdominal Tuberculosis

Abdominal tuberculosis is not a rare disease, but obstructive jaundice caused by tuberculosis (tuberculous lymphadenitis, tuberculous enlargement of the head of pancreas, and/or tuberculous stricture of the biliary tree) is rare. We recently experienced a case of obstructive jaundice as a result of paradoxical reaction of periportal tuberculous lymphadenopathy that was treated successfully with corticosteroid and biliary drainage. No similar cases have been reported previously.

Effects of low-dose corticosteroids on the bone mineral density of patients with rheumatoid arthritis: a meta-analysis.

BACKGROUND: : The effects of long-term high-dose corticosteroids on bone mineral density (BMD) are clear, but the effects of low-dose corticosteroids in patients with rheumatoid arthritis (RA) remain controversial. The aim of this study was to assess the effects of low-dose corticosteroids on BMD in patients with RA. METHODS: : The authors surveyed randomized controlled studies that examined the effects of low-dose corticosteroids on BMD in patients with RA using MEDLINE and the Cochrane Controlled Trials Register and by performing manual searches. Data were collected on BMD (end-of-period or change-from-baseline) after longest recorded treatment durations. Meta-analysis was performed using a random effects model; outcomes are presented as standardized mean differences (SMDs). RESULTS: : Seven studies were included in this meta-analysis, which included 7 studies on lumbar BMD meta-analysis and 6 studies on femur BMD meta-analysis. Corticosteroids resulted in a moderate worsening in lumbar BMD compared with controls (SMD = -0.483; 95% confidence interval [CI], -0.815 to -0.151, P = 0.004), whereas the femoral BMD differences were not siginificant (SMD = -0.224; 95% CI, -0.663 to 0.215, P = 0.318). Subgroup analysis of BMD data performed on a change-from-baseline basis showed that corticosteroids had a clear effect on both lumbar and femoral BMDs (SMD = -0.354; 95% CI, -0.620 to -0.088, P = 0.009; SMD = -0.488; 95% CI, -0.911 to -0.065, P = 0.024, respectively). CONCLUSIONS: : This meta-analysis shows BMD loss after low-dose corticosteroid treatment in patients with RA. These findings have practical implications for the long-term management of patients with RA on low-dose corticosteroids.

Association between serum uric acid and the Adult Treatment Panel III-defined metabolic syndrome: results from a single hospital database.

Hyperuricemia is known to be associated with various metabolic abnormalities of the metabolic syndrome, but its precise contribution is not well defined. We have investigated the effects of serum uric acid on the metabolic syndrome as defined by the Adult Treatment Panel (ATP) III criteria and tested its independent association. This was a cross-sectional study consisting of 1686 Korean subjects (821 men and 865 women) from a health promotion center. Clinical data and the presence of the metabolic syndrome were assessed, and serum uric acid was tested for its independent contribution to the metabolic syndrome using 2 multiple logistic regression models. The metabolic syndrome was defined by the original ATP III criteria and the modified ATP III criteria that include a reduced waist circumference. The general age-adjusted prevalence of the metabolic syndrome was 4.4% in men and 6.8% in women; hyperuricemic subjects tended to have a higher prevalence of the metabolic syndrome and more metabolic abnormalities than normouricemic subjects. The prevalence of the metabolic syndrome increased as normouricemia (2.9%) progressed to hyperuricemia (8.9%) and to gout (43.6%) in men. Multivariate analysis showed that serum uric acid was a significant factor for the development of the metabolic syndrome as defined by the original ATP III criteria only in one model for women (odds ratio, 1.51; 95% confidence interval, 1.11-2.05; P = .009). Serum uric acid is closely linked to and may even be independently associated with the metabolic syndrome as defined by the ATP III criteria, but only in women.

Meta-analysis of the combination of TNF inhibitors plus MTX compared to MTX monotherapy, and the adjusted indirect comparison of TNF inhibitors in patients suffering from active rheumatoid arthritis.

This present study was designed to examine (1) whether a combination therapy of TNF (tumor necrosis factor) blockers and methotrexate (MTX) is better than MTX monotherapy, and (2) if the TNF inhibitors such as etanercept, infliximab and adalimumab are all same for treating patients with active rheumatoid arthritis (RA). We performed meta-analysis of a combination therapy of TNF-blockers and MTX compared to MTX monotherapy and we performed adjusted indirect comparison of the TNF-blocking agents for their efficacy and toxicity. Three studies met the inclusion criteria for the analysis. Meta-analysis showed that the combination of MTX with anti-TNF inhibitors was more effective than MTX monotherapy and this indicated that combination therapy of anti-TNF inhibitors and MTX was comparable with MTX monotherapy in terms of withdrawal due to the side effects (RR: 1.05, 95% CI: 0.52-2.09, P = 0.86). The adjusted indirect comparison did not show any differences between infliximab and adalimumab. However, there was a significant difference for clinical efficacy and side effects between etanercept, adalimumab and infliximab. The RRs for achieving ACR20, ACR50 and ACR70 responses and withdrawal due to the side effect in the etanercept group were lower when compared with the adalimumab group. The RR for achieving an ACR20 response in the etanercept group was lower when compared with the infliximab group. The adjusted indirect comparison analysis suggests that the TNF-blocking agents all are not the same with respect to effectiveness and toxicity for the treatment of active RA.