Han Joo Baek

Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behçet's disease

Objectives To identify non-major histocompatibility complex susceptible genes that might contribute to Behçets disease (BD). Methods We performed a genome-wide association study using DNA samples from a Korean population consisting of 379 BD patients and 800 controls. A replication study was performed in a Japanese population (363 BD patients and 272 controls). To evaluate the functional implication of the target single nucleotide polymorphisms (SNP), gene expression levels in peripheral T cells, allele-specific modulation of promoter activity and biological effect of mRNA knockdown were investigated. Results We found a novel association of BD to the GIMAP locus, mapped to chromosome 7q36.1 (rs1608157, p=6.01×10−8 in a minor allele dominant model; rs11769828, allele based p=1.60×10−6). A fine mapping study identified an association with four additional SNP: rs1522596 (OR=1.45, p=7.70×10−6) in GIMAP4; rs10266069 (OR=1.32, p=2.67×10−4) and rs10256482 (OR=1.27, p=5.27×10−4) in GIMAP2; and rs2286900 (OR=1.61, p=3.53×10−5) in GIMAP1 areas. Replication study using DNA samples from the Japanese population validated the significant association between BD and the GIMAP locus. The GIMAP4 promoter construct plasmid with the minor allele of rs1608157 displayed significantly lower activity than one with the major allele. Moreover, CD4 T cells from BD patients showed a lower level of GIMAP4 mRNA, and GIMAP4 knockdown was protective against Fas-mediated apoptosis. Conclusions These results suggest that a GIMAP cluster is a novel susceptibility locus for BD, which is involved in T-cell survival, and T-cell aberration can contribute to the development of BD.

Spondylitis is the most common pattern of psoriatic arthritis in Korea

Abstract We assessed the prevalence and clinical features of psoriatic arthritis (PsA) in Korean patients with psoriasis. The prevalence of PsA in patients with psoriasis was 9%. Patients with PsA were older and had a longer duration of skin disease than those with psoriasis alone (median age, 40 vs 35 years, P = 0.03, and 15.3 vs 11.7 years, P = 0.04, respectively). Spondylitis was the most common pattern of PsA (50%). Nail change, dactylitis, and enthesopathy were observed in 36%, 15.4%, and 15.6% of patients with PsA, respectively. Increased erythrocyte sedimentation rate (ESR), antinuclear antibody, and radiological sacroiliitis were more frequent in patients with PsA than in those with uncomplicated psoriasis (25.8% vs 10.3%, P = 0.04; 37.9% vs 16.7%, P = 0.02; and 37.8% vs 1.1%, P < 0.01, respectively). The onset ages of psoriasis and arthritis in the spondylitis group were significantly lower than those in the non-spondylitis group (median age, 21.5 vs 31 years, P = 0.03, and 28.5 vs 43.5 years, P = 0.01, respectively). HLA-B27 was prevalent in 8% of patients with PsA.

Assessment of comparative pain relief and tolerability of SKI306X compared with celecoxib in patients with rheumatoid arthritis : A 6-week, multicenter, randomized, double-blind, double-dummy, phase III, noninferiority clinical trial

BACKGROUND SKI306X, which consists of biologically active ingredients from Clematis mandsburica, Tricbosantbes kirilowii, and Prunella vulgaris, was developed and tested in preclinical trials in Korea. Those studies found that SKI306X was associated with an anti-inflammatory and analgesic effect, and that it can delay the destruction of cartilage in rheumatoid arthritis (RA). OBJECTIVE The aim of this study was to compare the pain relief and tolerability of SKI306X and celecoxib in patients with RA. METHODS This study was a 6-week, multicenter, randomized, double-blind, double-dummy, Phase III, noninferiority clinical trial. Eligible patients were aged 18 to 80 years, had a history of RA with a disease duration of > or =3 months, and were functional American College of Rheumatology (ACR) class I, II, or III before entry. After a washout period of 2 weeks, patients were randomized to SKI306X 200 mg TID or celecoxib 200 mg BID for 6 weeks. The primary end point was a change in patient assessment of pain intensity using a visual analog scale (VAS). The secondary end points were a 20% improvement in response rate as defined by the ACR (ACR20) and the frequency of rescue medication use. Results after 3 and 6 weeks of treatment were compared with baseline and between treatment groups, and all patients were assessed for adverse events (AEs), clinical laboratory data, and vital signs. AEs were identified based on spontaneous reports by patients during interviews conducted by the investigators and the study coordinator. RESULTS Two hundred twenty-two Korean patients from 7 medical centers were assessed and 183 were enrolled and randomized to 1 of 2 treatment groups. Ninety-one patients (10 male, 81 female; mean [SD] age, 52.13 [12.64] years; mean [SD] duration of RA, 9.08 [10.23] years; no. [%] of ACR class I, II, and III, 13 [14.29], 44 [48.35] and 34 [37.36] patients, respectively) received SKI306X 200 mg TID and 92 patients (10 male, 82 female; mean [SD] age, 51.78 [10.94] years; mean [SD] duration of RA, 8.78 [7.78] years; no. [%] of ACR class I, II, and III, 14 [15.22], 44 [47.83], and 34 [36.96] patients, respectively) received celecoxib 200 mg BID. An analysis of the change in reported pain intensity as determined by VAS (mm) score between baseline and week 3 (mean [SD], 13.64 [16.62] vs 14.45 [15.89]), and between baseline and week 6 (18.4 [20.8] vs 17.9 [19.1], respectively) suggested that SKI306X was not inferior to celecoxib. The number of patients who achieved ACR20 response rate was not significantly different between the SKI306X group and the celecoxib group at week 3 (16/87 [18.4%] vs 24/87 [27.6%], respectively) and at week 6 (29/87 [33.3%] vs 29/87 [33.3%]). The frequency of rescue medication use was not significantly different between the SKI306X group and celecoxib group at week 3 (54/87 [62.1%] vs 47/87 [54.0%], respectively) or week 6 (57/87 [65.5%] vs 49/87 [56.3%]). Drug-related AEs were reported by 27 (29.7%) patients in the SKI306X group and 22 (23.9%) patients in the celecoxib group. The most frequent drug-related AEs were epigastric pain (9/91 [9.9%]) in the SKI306X group and glutamyltranferase elevation (4/92 [4.3%]) in the celecoxib group. No significant between-group differences were observed in the prevalence of drug-related clinical- or laboratory-determined AEs. CONCLUSION The results of this study suggest that SKI306X was generally well tolerated and not inferior to celecoxib in regard to pain relief in these Korean patients with RA.

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

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

POEMS syndrome complicated by extensive arterial thromboses

POEMS syndrome—characterised by polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes—is a rare multi-systemic disease. Its skin change is often like that of connective tissue diseases such as scleroderma. Although clinical manifestations of POEMS syndrome are known to be diverse, arterial or venous thrombosis is a less-recognised feature. We report a 41-year-old man with scleroderma-like skin change who was initially negative for monoclonal protein, but finally confirmed as having POEMS syndrome. During the disease course, he was complicated by extensive arterial thromboses including stroke. This case evokes the need to include POEMS syndrome in the differential diagnoses in patients with scleroderma-like skin change and to repeat measurements of monoclonal protein to confirm its diagnosis. A POEMS patient with extensive arterial thromboses may have a catastrophic disease course, requiring earlier diagnosis and more aggressive treatment.

Molecular and genetic characterization of two anti-DNA antibodies derived from patients with systemic lupus erythematosus

Abstract Anti-double stranded(ds) DNA antibody is one of markers of systemic lupus erythematosus (SLE). Two human monoclonal anti-DNA antibody – producing cell lines were established from two SLE patients. One cell line secreted IgG isotype antibody (KSUG) and the other secreted IgM isotype antibody (KSUN). The light chains of the two immunoglobulins were lambda chains. The nucleotide sequences for the immunoglobulin variable region genes of the two antibodies were determined and compared to germline sequences. The heavy and lambda light chains of KSUG were VH3 family and V λ IIIb, respectively. The heavy and lambda light chains of KSUN were VH4 family and V λ IX, respectively. Antibody KSUG, IgG isotype, showed somatic mutations, whereas KSUN, IgM isotype, used the germline gene without mutation. These findings reconfirm the current paradigms that IgM anti-DNA antibodies are produced by utilizing germline genes whereas IgG anti-DNA antibodies are produced by somatic mutations.

Overexpression and Unique Rearrangement of VH2 Transcripts in Immunoglobulin Variable Heavy Chain Genes in Ankylosing Spondylitis Patients

To identify immunoglobulin variable heavy chain (VH) gene usages in Korean ankylosing spondylitis (AS) patients, expression level of VH2 genes from peripheral blood mononuclear cells (PBMCs) of 8 AS patients and 9 healthy donors was analysed by quantitative real-time PCR (Q-PCR). Q-PCR results demonstrated VH2 genes were overexpressed in AS patients (Relative amount of mRNA of VH2 genes to a house-keeping gene, 7.13 ± 7.77 vs, 0.68 ± 0.55; P < 0.0001). The sequence analysis revealed the majority of them contained CDC42 binding protein kinase beta (CDC42 BPB) genes. The insertion of CDC42 BPB gene was confirmed by PCR with primers corresponding CDC42 BPB and CH genes. Our study revealed VH2 overexpression and unique rearrangement in Ig VH genes from peripheral blood of AS patients. This may imply aberrant immunoglobulin gene rearrangement in B cell occurs in Korean AS patients, which requires further investigation.

Clinical significance of anti-filaggrin antibody recognizing uncitrullinated filaggrin in rheumatoid arthritis

Filaggrin is expressed in the cornified layer of epidermis and known to be one of the antigenic targets in rheumatoid arthritis. Although the citrulline residue in filaggrin is thought to be an antigenic determinant recognized by autoantibodies, the diagnostic sensitivity of synthetic citrullinated peptide is variable. To investigate the implication of anti-filaggrin antibodies recognizing uncitrullinated filaggrin in rheumatoid arthritis, we assayed antibody titers using unmodified recombinant filaggrin in the sera from 73 patients with rheumatoid arthritis, 150 patients with other connective tissue diseases and 70 normal controls. We also performed the correlation analysis between antibody titers and the clinical variables in patients with rheumatoid arthritis. Titers of IgG anti-filaggrin antibodies were significantly higher in rheumatoid arthritis patients compared to normal controls (P=0.02), but not in patients with osteoarthritis, ankylosing spondylitis or systemic lupus erythematosus. IgG anti-filaggrin antibodies were more frequently found in patients with rheumatoid arthritis compared to normal controls (12.3% vs 1.4% respectively, P=0.04). An anti-filaggrin antibody titer was correlated with visual analogue scale of pain, tender joint count, Ritchie articular index or C-reactive protein, but not with anti-nuclear antibody or rheumatoid factor. These results suggest that anti-filaggrin antibody recognizes the uncitrullinated filaggrin as an antigen and its titer correlates with clinical parameters, explaining the variable sensitivity of anti-filaggrin antibody test.

Monthly Oral Ibandronate Reduces Bone Loss in Korean Women With Rheumatoid Arthritis and Osteopenia Receiving Long-term Glucocorticoids: A 48-week Double-blinded Randomized Placebo-controlled Investigator-initiated Trial

PURPOSE Our aim was to investigate the efficacy of monthly oral ibandronate in Korean women with rheumatoid arthritis and reduced bone mineral density (BMD) receiving long-term glucocorticoids. METHODS Patients (n = 167 women) were randomly assigned (1:1) to receive ibandronate 150 mg or placebo every 4 weeks. Patients had taken glucocorticoid (equivalent of daily prednisolone ≥5 mg) for 3 or more consecutive months before enrollment, and had a lumbar spine 1 to 4 (L1-L4) T-score of < -1.0 and ≥ -2.5. Both groups were provided with daily calcium carbonate and cholecalciferol. The primary end point was the L1 to L4 BMD percent changes at 48 weeks compared with baseline. FINDINGS Baseline characteristics were comparable between the 2 groups. BMD percent changes in L1 to L4 at 48 weeks were significantly different between the ibandronate versus the placebo group (+3.7% [5.1%] vs -1.9% [4.4%], respectively; P < 0.0001). BMD percent changes at 48 weeks in femur neck and total hip also had similar results (P = 0.0073 and P = 0.0031, respectively). Decrease of serum type 1 collagen C-terminal telopeptide was significant at both 24 and 48 weeks in the ibandronate group. There was no incident of fragility fracture in both groups during the study period. Safety profiles, including adverse events, were comparable between the 2 groups. IMPLICATIONS Monthly oral ibandronate for 48 weeks is well tolerated and effective in reducing bone mineral loss in women with rheumatoid arthritis on long-term glucocorticoid therapy. Longer follow-up studies are needed to investigate the benefit of ibandronate on fracture rate reduction in this subset of patients. ClinicalTrials.gov identifier: NCT01287533.

Seasonality of Gout in Korea: A Multicenter Study

The object of this study was to evaluate the seasonality of gout in Korea. We retrospectively examined data from 330 patients seen at nine rheumatology clinics, treated with urate lowering therapy (ULT) more than one year after stopping prophylactic medication. Demographic data, clinical and laboratory features, and seasonality of gout onset and flares were collected. Season was classified in three-month intervals. The mean age was 52.2 yr and mean disease duration was 26.8 months. The male to female count was 318:12. The onset of acute gouty attacks was obtained in 256 patients. Gout developed most commonly in summer season (36.7%) (P<0.001) and in June (15.6%, P=0.002). During ULT, there were 147 (male 97.3%) gout flares. Although there was no statistically significant difference, gout flares were more common in summer (30.6%). Aggravating factors were identified in 57 flares: alcohol (72.0%) was most common. In the patients who attained target serum uric acid (<6 mg/dL) at the end of prophylaxis, gout flares were high in fall (35.8%) and September (17.0%). In Korea, the summer is most common season of gout onset and there is a tendency for gout flares to increase during ULT in summer/fall season. Graphical Abstract