Polymyalgia rheumatica is an inflammatory disease affecting elderly and involving the shoulder and pelvic girdles. No epidemiological study of polymyalgia rheumatica was conducted in Korea. We retrospectively evaluated patients with polymyalgia rheumatica followed up at the rheumatology clinics of 10 tertiary hospitals. In total 51 patients, 36 patients (70.6%) were female. Age at disease onset was 67.4 yr. Twenty-three patients (45.1%) developed polymyalgia rheumatica in winter. Shoulder girdle ache was observed in 45 patients (90%) and elevated erythrocyte sedimentation rate (> 40 mm/h) in 49 patients (96.1%). Initial steroid dose was 23.3 mg/d prednisolone equivalent. Time to normal erythrocyte sedimentation rate was 4.1 months. Only 8 patients (15.7%) achieved remission. Among 41 patients followed up, 28 patients (68.3%) had flare at least once. Number of flares was 1.5 ± 1.6. The frequency of flare was significantly lower in patients with remission (P = 0.02). In Korea, polymyalgia rheumatica commonly develops during winter. Initial response to steroid is fairly good, but the prognosis is not benign because remission is rare with frequent relapse requiring long-term steroid treatment.
Polymyalgia Rheumatica; Symptoms; Treatment; Steroids; Remission; Prognosis
Liver X receptors are established sensors of lipid and cholesterol homeostasis. Recent studies have reported that these receptors are involved in the regulation of inflammation and immune responses. We attempted to identify single nucleotide polymorphisms (SNPs) of the NR1H3 gene associated with the susceptibility to systemic lupus erythematosus (SLE).
SNPs were genotyped using SNaPSHOT assay in 300 Korean patients with SLE and 217 normal controls (NC), and in replication samples (160 SLE patients and 143 NC). Also, the functional effects of NR1H3 gene promoter polymorphisms were analyzed using a luciferase assay, real-time polymerase chain reaction, B cell proliferation assay and an electrophoretic mobility shift assay.
We identified five polymorphisms: -1851 T > C (rs3758673), -1830 T > C (rs3758674), -1003 G > A (new), -840 C > A (rs61896015) and -115 G > A (rs12221497). There was a significant and reproducible difference in the -1830 T > C, -1003 G > A and -115 G > A polymorphisms between the SLE and the NC. Luciferase activity of the structure containing -1830 C was less enhanced compared to the structure containing -1830 T in basal, GW3965 and T0901317 treated Hep3B cells (P = 0.009, P = 0.034 and P <0.001, respectively). Proliferation of the -1830 TC type was increased compared to the -1830 TT type in basal, GW3965 and T0901317 treated B cells from SLE patients (P = 0.011, P = 0.040 and P = 0.017, respectively). Transcription factor GATA-3 preferentially bound the -1830 T allele in the promoter.
NR1H3 genetic polymorphisms may be associated with disease susceptibility and clinical manifestations of SLE. Specifically, -1830 T > C polymorphism within NR1H3 promoter region may be involved in regulation of NR1H3 expression.
Systemic lupus erythematosus (SLE) is a typical autoimmune disease that's characterized by various autoantibodies to nuclear and cytoplasmic antigens. The presence of antinuclear antibodies (ANA) in serum is generally considered a decisive diagnostic sign of SLE. However, a small subset of SLE patients who had the typical clinical features of SLE was reported to show persistently negative ANA tests. Our report describes a 16-yr-old female who presented with the clinical manifestations of SLE such as malar rash, photosensitivity, arthritis, lymphopenia, pericarditis and proteinuria. The serum autoantibodies were all negative and renal biopsy showed that the histopathological changes of immune complex mediated the focal segmental necrotizing glomerulonephritis with crescent formation. She was treated with monthly pulse cyclophosphamide along with corticosteroids. During the 2-yr follow-up period, the proteinuria was markedly decreased and all of the ANA and anti-double stranded DNA antibody tests were negative. This case suggests that ANA may not be required in the pathogenesis of lupus nephritis.
Antinuclear antibody; Lupus nephritis; Systemic lupus erythematosus
We investigated the agreement between the QuantiFERON-TB Gold (QFT-Gold) test and the tuberculin skin test (TST) in the diagnosis of latent tuberculosis infection in patients with rheumatoid arthritis (RA), compared with healthy controls, in Korea.
We recruited 64 patients with RA and 79 healthy controls at two university hospitals in South Korea. The participants underwent both the QFT-Gold test and the TST simultaneously between August 2006 and February 2009. All patients were diagnosed using the classification criteria for RA revised in 1987 by the American College of Rheumatology. Bacillus Calmette-Guérin vaccination status and current medications were evaluated, and disease activities were assessed using the Disease Activity Score in 28 joints. Eleven patients with RA produced indeterminate QFT-Gold test results and were thus excluded from the kappa analysis.
Based on an induration of 10 mm in diameter as the TST cutoff value, the QFT-Gold test and TST demonstrated 75.0% agreement (κ = 0.23) in patients with RA and 75.9% agreement (κ = 0.19) in healthy controls. Among the 56 patients with RA who had negative TST results, 11 patients (17.2%) also yielded indeterminate QFT-Gold results.
Our study showed poor agreement between the results of the QFT-Gold test and the TST in both RA patients and healthy controls. Based on these findings, we emphasize the importance of making clinical decisions in the diagnosis of latent tuberculosis in Koreans with or without RA.
QuantiFERON-TB Gold test; Tuberculin skin test; Latent tuberculosis; Arthritis, rheumatoid
Serum rheumatoid factor (RF) is important in the diagnosis and prognosis of rheumatoid arthritis (RA). The purpose of this study is to compare the clinical characteristics and treatment patterns of RA according to the presence of RF in Korean patients. A retrospective analysis was performed on the records of 109 patients who were followed for at least 2 years, among 230 RA patients who visited at the rheumatology clinic in Ajou University Hospital and who fulfilled the 1987 revised American College of Rheumatology criteria for RA. Sixty-four patients were RF positive (58.7%) and 91 patients were female (83.5%). There was no significant difference in demographic characteristics, joint involvements, or percentage of morning stiffness between seropositive and seronegative groups. Anti-nuclear antibody was detected more frequently in the seropositive group (p<0.05). At initial diagnosis, the seropositive group had higher white blood cell and platelet counts than the seronegative group (p<0.01). However, the difference was disappeared at the last follow-up. Inflammatory markers such as ESR and CRP were also higher at diagnosis in the seropositive group (p<0.01). These inflammatory markers were still greater than the seronegative group at the last follow-up (p<0.01). There was no significant difference in the use of disease modifying antirheumatic drug (DMARD) and steroid dosage between groups. However, DMARD combination therapy was more commonly used in the seropositive group (p<0.05), especially triple DMARD combination. These results suggest that disease activity is more severe in the seropositive than the seronegative group, and more aggressive treatments are needed in the seropositive group.
Rheumatoid arthritis; rheumatoid factor; inflammation; antirheumatic drug; combination therapy
Objective. Although two recent randomized placebo-controlled trials of rituximab (RTX) failed to demonstrate efficacy in systemic lupus erythematosus (SLE), clinicians continue to use off-label RTX for cases refractory to current treatments. We evaluated the effectiveness and safety of rituximab for patients with refractory SLE in Korea. Methods. We retrospectively analyzed multicenter patients treated with RTX in Korea. Results. 39 SLE patients treated with RTX were included in the following manner: lupus nephritis 43.6%, hematologic 33.3%, arthritis 7.8%, myositis 7.8%, and others 7.7%. All patients had responded poorly to at least one conventional immunosuppressive agent (mean 2.5 ± 1.1, cyclophosphamide 43.6%, mycophenolate mofetil 48.7%, and other drugs) before RTX. Clinical improvements (complete or partial remission) occurred in patients with renal disease, hematologic disease, arthritis, myositis, and other manifestations at 6 months after RTX. The SLEDAI score was significantly decreased from 10.8 ± 7.1 at baseline to 6.7 ± 4.0 at 6 months, 6.2 ± 4.1 at 12 months, and 5.5 ± 3.6 at 24 months after RTX (P < 0.05). Among 28 clinical responders, 4 patients experienced a relapse of disease at 25 ± 4 months. Infections were noted in 3 patients (7.7%).
Conclusion. RTX could be an effective and relatively safe therapeutic option in patients with severe refractory SLE until novel B-cell depletion therapy is available.
Systemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin αΜ (complement component 3 receptor 3 subunit) encoding a ligand for intracellular adhesion molecule (ICAM) proteins, is an established SLE susceptibility locus. This study aimed to evaluate the independent and joint effects of genetic variations in the genes that encode ITGAM and ICAM.
The authors examined several markers in the ICAM1–ICAM4–ICAM5 locus on chromosome 19p13 and the single ITGAM polymorphism (rs1143679) using a large-scale case–control study of 17 481 unrelated participants from four ancestry populations. The single marker association and gene–gene interaction were analysed for each ancestry, and a meta-analysis across the four ancestries was performed.
The A-allele of ICAM1–ICAM4–ICAM5 rs3093030, associated with elevated plasma levels of soluble ICAM1, and the A-allele of ITGAM rs1143679 showed the strongest association with increased SLE susceptibility in each of the ancestry populations and the trans-ancestry meta-analysis (ORmeta=1.16, 95% CI 1.11 to 1.22; p=4.88×10−10 and ORmeta=1.67, 95% CI 1.55 to 1.79; p=3.32×10−46, respectively). The effect of the ICAM single-nucleotide polymorphisms (SNPs) was independent of the effect of the ITGAM SNP rs1143679, and carriers of both ICAM rs3093030-AA and ITGAM rs1143679-AA had an OR of 4.08 compared with those with no risk allele in either SNP (95% CI 2.09 to 7.98; p=3.91×10−5).
These findings are the first to suggest that an ICAM–integrin-mediated pathway contributes to susceptibility to SLE.
Little is known about hair mineral status in fibromyalgia patients. This study evaluated the characteristics of hair minerals in female patients with fibromyalgia compared with a healthy reference group. Forty-four female patients diagnosed with fibromyalgia according to the American College of Rheumatology criteria were enrolled as the case group. Ageand body mass index-matched data were obtained from 122 control subjects enrolled during visit for a regular health check-up. Hair minerals were analyzed and compared between the two groups. The mean age was 43.7 yr. General characteristics were not different between the two groups. Fibromyalgia patients showed a significantly lower level of calcium (775 µg/g vs 1,093 µg/g), magnesium (52 µg/g vs 72 µg/g), iron (5.9 µg/g vs 7.1 µg/g), copper (28.3 µg/g vs 40.2 µg/g) and manganese (140 ng/g vs 190 ng/g). Calcium, magnesium, iron, and manganese were loaded in the same factor using factor analysis; the mean of this factor was significantly lower in fibromyalgia group in multivariate analysis with adjustment for potential confounders. In conclusion, the concentrations of calcium, magnesium, iron, and manganese in the hair of female patients with fibromyalgia are lower than of controls, even after adjustment of potential confounders.
Fibromyalgia; Fibromyalgia Syndrome; Trace Minerals; Calcium; Magnesium
We performed a multicenter cross-sectional study of 134 sexually active systemic lupus erythematosus (SLE) patients to investigate the prevalence of and risk factors for high risk human papilloma virus (HPV) infection and cervical cytological abnormalities among Korean women with SLE. In this multicenter cross-sectional study, HPV testing and routine cervical cytologic examination was performed. HPV was typed using a hybrid method or the polymerase chain reaction. Data on 4,595 healthy women were used for comparison. SLE patients had greater prevalence of high-risk HPV infection (24.6% vs. 7.9%, P<0.001, odds ratio 3.8, 95% confidence interval 2.5-5.7) and of abnormal cervical cytology (16.4 vs. 2.8%, P<0.001, OR 4.4, 95% CI 2.5-7.8) compared with controls. SLE itself was identified as independent risk factors for high risk HPV infection among Korean women (OR 3.8, 95% CI 2.5-5.7) along with ≥2 sexual partners (OR 8.5, 95% CI 1.2-61.6), and Pap smear abnormalities (OR 97.3, 95% CI 6.5-1,456.7). High-risk HPV infection and cervical cytological abnormalities were more common among Korean women with SLE than controls. SLE itself may be a risk factor for HPV infection among Korean women, suggesting the importance of close monitoring of HPV infections and abnormal Pap smears in SLE patients.
Systemic Lupus Erythematosus, Human Papilloma Virus; Cervical Cytological Abnormalities
The TAM (tyro 3, axl, mer) kinases are key regulators of innate immunity and are important in the phagocytosis of apoptotic cells. Gas6 and protein S are ligands for these TAM kinases and bind to phosphatidyl serine residues exposed during apoptosis. In animal models, absence of TAM kinases is associated with lupus-like disease. To test whether human systemic lupus erythematosus (SLE) patients might have deficient levels of TAM ligands, we measured Gas 6 and protein S levels in SLE.
107 SLE patients were recruited. Of these, 45 SLE patients were matched age, gender and ethnicity with normal controls (NC). Gas6 and free protein S were measured with sandwich enzyme linked immunosorbent assays (ELISAs).
Overall, the plasma concentrations of Gas6 and free protein S were not different between 45 SLE patients and 45 NC. In SLE patients, the levels of free protein S were positively correlated with age (r = 0.2405, P = 0.0126), however those of Gas6 were not. There was no correlation between the concentrations of Gas6 and free protein S in individuals. Levels of free protein S were significantly lower in SLE patients with a history of serositis, neurologic disorder, hematologic disorder and immunologic disorder. Gas6 levels were elevated in patients with a history of neurologic disorder. The SLE patients with anti-Sm or anti-cardiolipin IgG showed lower free protein S levels. Circulating free protein S was positively correlated with complement component 3 (C3) (r = 0.3858, P < 0.0001) and complement component 4 (C4) (r = 0.4275, P < 0.0001). In the patients with active BILAG hematologic involvement, the levels of free protein S were lower and those of Gas6 were higher.
In SLE, free protein S was decreased in patients with certain types of clinical history and disease activity. Levels of free protein S were strongly correlated with C3 and C4 levels. Gas6 levels in SLE patients differed little from levels in NC, but they were elevated in the small numbers of patients with a history of neurological disease. The correlation of decreased protein S levels with lupus disease activity is consistent with a role for the TAM receptors in scavenging apoptotic cells and controlling inflammation. Protein S appears more important functionally in SLE patients than Gas6 in this regard.
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 Schober's 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.
To evaluate the clinical significance of autoantibodies to three major epithelial cytokeratins (CK) - CK8, CK18, and CK19 - we compared 66 patients with toluene diisocyanate (TDI)-induced asthma (group I) with three control groups: 169 asymptomatic exposed subjects (group II), 64 patients with allergic asthma (group III), and 123 unexposed healthy subjects (group IV). Serum IgG, specific for human recombinant CKs, were measured by ELISA (enzyme linked immunosorbent assay), and ELISA inhibition tests were performed. The existence of these antibodies was confirmed by IgG immunoblot analysis. Anti-TDI-HSA (human serum albumin) IgE and IgG antibodies were measured by ELISA in the same set of the patients. The prevalence of CK8, CK18, and CK19 auotantibodies in group I was significantly higher than in the other three groups. Results of the ELISA inhibition test showed significant inhibition with the addition of three CKs in a dose-dependent manner. No significant association was found between CK autoantibodies and the prevalence of anti-TDI-HSA IgG and IgE antibodies. These results suggest that autoantibodies to CK18 and CK19 can be used as serologic markers for identifying patients with TDI-induced asthma among exposed workers.
Isocyanate; asthma; cytokeratin; diagnosis
Japanese hop (Hop J) pollen has been considered as one of the major causative pollen allergens in the autumn season. We developed a new Hop J immunotherapy extract in collaboration with Allergopharma (Reinbeck, Germany) and investigated immunologic mechanisms during 3 yr immunotherapy. Twenty patients (13 asthma with rhinitis and 7 hay fever) were enrolled from Ajou University Hospital. Sera were collected before, 1 yr, and 3 yr after the immunotherapy. Changes of serum specific IgE, IgG1, and IgG4 levels to Hop J pollen extracts and serum IL-10, IL-12, TGFβ1 and soluble CD23 levels were monitored by ELISA. Skin reactivity and airway hyper-responsiveness to methacholine were improved during the study period. Specific IgG1 increased at 1 yr then decreased again at 3 yr, and specific IgG4 levels increased progressively (p<0.05, respectively), whereas total and specific IgE levels showed variable responses with no statistical significance. IL-10, TGF-β1 and soluble CD23 level began to decrease during first year and then further decreased during next two years with statistical significances. (p<0.05, respectively). In conclusion, these findings suggested the favorable effect of long term immunotherapy with Hop J pollen extracts can be explained by lowered IgE affinity and generation of specific IgG4, which may be mediated by IL-10 and TGF-β1.
Desensitization, Immunologic; Allergen Immunotherapy; Pollen; Specific IgG; Interleukin-10; transforming growth factor beta 1
Several studies have suggested the involvement of an autoimmune mechanism in aspirin (ASA)-intolerant asthma. To test this hypothesis, we measured the levels of circulating autoantibodies, such as IgG and IgA to tissue transglutaminase (TGase), IgG to cytokeratins (CKs) 8, 18, and 19, Clq-binding immune complex (CIC), and antinuclear antibody (ANA), in the sera of 79 patients with ASA-intolerant asthma (Group I) and those of two control groups, consisting of 61 patients with ASA-tolerant asthma (Group II) and 88 healthy control subjects (Group III) by means of ELISA. Significantly higher prevalences of IgG antibodies to CK18 (13.9%) and CK19 (17.7%) were noted in Group I, as compared with Group III (p<0.05 for all) not with Group II. Regarding the prevalences of other autoantibodies, the levels of ANA (1.3%), IgG to TGase (3.8%), and CIC (24.7%) in Group I were not significantly different from those in Groups II and III. Significant correlations were found between positivities for the anti-CK18 and anti-CK19 autoantibodies and the PC20 methacholine values in the analysis of asthma Groups I and II vs. normal controls, (p=0.001 and p=0.003, respectively). Further studies are needed to explore the potential involvement of an autoantibody-mediated mechanism in the clinical manifestation of bronchial asthma.
Aspirin; Bronchoconstriction; Aspirin-intolerant Asthma; Autoantibodies; Cytokeratin; Keratin
The pathogenesis of aspirin (acetylsalicylic acid, ASA)-intolerant urticaria (AIU) is still poorly understood but it has recently been suggested that it is associated with the overproduction of leukotriene (LT). This is supported by evidence that cyclooxygenase 2 inhibitor is given safely to patients with AIU. The present study was designed to investigate the role of genetic polymorphism of LT related genes in the pathogenesis of AIU via a case-control study. We screened single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in leukotriene synthesis in the Korean population with AIU (n=101), ASA-intolerant asthma (AIA, n=95) and normal healthy controls (n=123). Genotype was determined by primer extension reactions using the SNapShot ddNTP primer extension kit. Among 8 SNPs of four LT related genes, the polymorphism of ALOX5 at positions of -1708 G>A showed significant difference in genotype frequency between AIU and AIA (p=0.01). Furthermore, there were significant differences observed in the frequencies of two ALOX5 haplotypes between the AIU group and AIA group (p<0.05). However, there were no differences in allele, genotype, or haplotype frequencies of ALOX5 between the AIU group and the normal control group. These results suggested that ALOX5 has a differing contribution in two major clinical pathogenesis related to ASA-sensitivity.
Aspirin, Hypersensitivity; Urticaria; Polymorphism, Genetic; Leukotrienes
Glutathion S-transferase P1 (GSTP1), the abundant isoform of glutathione S-transferase in lung epithelium, plays an important role in cellular protection against oxidative stress and toxic foreign chemicals. GSTP1 (Ile105Val) polymorphism has been reported to be associated with asthma related phenotypes such as atopy and bronchial hyperresponsiveness. Therefore we investigated whether this polymorphism may be associated with the development of aspirin-intolerant asthma (AIA).
GSTP1 Ile105Val polymorphism was determined using a single based extension method in 88 AIA subjects and compared to 154 aspirin-tolerant asthma (ATA) subjects and 119 normal healthy controls (NC) recruited from the Korean population.
No significant differences in allele and genotype frequencies of the GSTP1 Ilel105Val polymorphism were observed in the three groups (p>0.05). However, minor G allele frequency of the GSTP1 Ilel105Val polymorphism in AIA group (16.5%) tended to be lower than in the NC group (20.6%).
These results suggest a lack of association of the GSTPI Ilel105Val gene polymorphism with AIA phenotype in the Korean population [word count: 159].
Aspirin-intolerant asthma; Hyperresponsiveness; Glutathione-S-transferase
The pathogenic mechanism of ASA-induced urticaria/angioedema (AIU) is still poorly understood, but it has been known that histamine releasing by cutaneous mast cell activation is considered to be an important role. Considering the importance of histamine in AIU, we speculated that a genetic abnormality of histamine-related genes such as a high-affinity IgE receptor, a metabolic enzyme of histamines and histamine receptors, may be involved in the development of AIU. Enrolled in the study were 110 patients with AIU, 53 patients without ASA hypersensitivity who had various drug allergies presenting as exanthematous skin symptoms, and 99 normal healthy controls (NC). Eleven single nucleotide polymorphisms (SNPs) of the β chain of the high-affinity IgE receptor (FCER1B) and three histamine-related genes-histamine N-methyltransferase (HNMT), histamine H1 receptor (HRH1), histamine H2 receptor (HRH2)-were screened using the SNP-IT assay based on a single base extension method. No significant differences were observed in allele and genotype frequencies, and haplotype frequencies of all the SNPs of FCER1B, HNMT, HRH1, and HRH2 among the three groups (p>0.05, respectively). These results suggest that the polymorphisms of FCER1B and the three histamine-related genes may not contribute to the development of AIU phenotype in the Korean population.
Aspirin; Hypersensitivity; Urticaria; Polymorphism, Genetic
Vascular endothelial growth factor (VEGF) is a multi-functional cytokine involved in inflammation, repair and angiogenesis in asthmatic airway. This study aimed to evaluate the role of VEGF in immediate bronchoconstriction induced by TDI inhalation, and in chronic TDI-asthma patients. 11 newly diagnosed TDI-asthma patients (group I), 12 chronic TDI-asthma patients with persistent asthma symptoms followed for >4 yr and 15 unexposed healthy controls were enrolled. In group I, induced sputum and serum were collected before and 7 hr after placebo- and TDI-bronchoprovocation test (BPT). In group II, induced sputum and serum were collected every 2 yr. VEGF levels were measured by ELISA. There were no significant differences in sputum and serum VEGF levels between patients and controls. Before and after placebo- and TDI-BPT, no significant changes were noted in sputum and serum VEGF levels of group I. In group II patients, sputum VEGF showed variable changes at 1-yr, then decreased significantly at 2-yr (p<0.05), while serum VEGF showed variable changes at 2-yr, which decreased significantly at 4-yr (p<0.05). These results suggest that VEGF may play a minor role in immediate bronchoconstriction after TDI-BPT. In chronic TDI-asthma, VEGF may be involved to 2 yr after the diagnosis and the contribution may decrease after then.
Vascular Endothelial Growth Factor; Toluene 2,4-Diisocyanate; Asthma, Exercise-Induced; Bronchoprovocation Test; Sputum