Pregnancy Outcomes Associated With Biologic Agent Exposure in Patients With Several Rheumatic Diseases and Inflammatory Bowel Diseases

Background@#This study aimed to analyze pregnancy outcomes based on biologic agents use in women using the nationwide population-based database. @*Methods@#The study used the claims database to identify women of childbearing age with several rheumatic (rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis) and inflammatory bowel diseases (Crohn’s disease and ulcerative colitis) who had pregnancy-related codes between January 2010 and December 2019. We analyzed live births and adverse pregnancy outcomes based on the previous use of biologics. We also stratified the patients according to duration of biologic agent exposure before pregnancy and the use of biologics during pregnancy to analyze the pregnancy outcomes by subgroups. @*Results@#We identified 4,787 patients with pregnancy events. Among them, 1,034 (21.6%) used biologics before pregnancy. Live birth rate was not different between the biologics group and biologics naïve group (75.0% vs. 75.2%). Multivariate analyses showed that biologics use was associated with higher risk of intrauterine growth retardation (odds ratio [OR], 1.780) and lower risk of gestational diabetes mellitus (OR, 0.776) compared with biologics naïve. Biologics use during pregnancy was associated with higher risk of preterm delivery (OR, 1.859), preeclampsia/eclampsia (OR, 1.762), intrauterine growth retardation (OR, 3.487), and cesarean section (OR, 1.831), but lower risk of fetal loss (OR, 0.274) compared with biologics naïve. @*Conclusions@#Although there was no difference in live birth rate between the biologics group and biologics naïve group, biologics use seems to be associated with several adverse pregnancy outcomes, especially in patients with biologics during pregnancy. Therefore, patients with biologics during pregnancy need to be carefully observed for adverse pregnancy outcomes.

Clinical and Genetic Risk Factors Associated With the Presence of Lupus Nephritis

Objective@#To elucidate whether clinical features and the weighted genetic risk score (wGRS) were associated with the presence of lupus nephritis (LN). @*Methods@#We retrospectively divided patients with systemic lupus erythematosus (SLE, n=1,078) into biopsy-proven LN (n=507) and non-LN groups (non-LN, n=571). Baseline clinical features, serologic markers, and the wGRS were collected. The wGRS was calculated from 112 non-human leukocyte antigen (non-HLA) loci and HLA-DRβ1 amino acid haplotypes for SLE. Associations among clinical features, wGRS, and the presence of LN were identified. @*Results@#In the multivariate analysis, patients with LN were younger at diagnosis (odds ratio [OR]=0.97, p＜0.001), had more pleuritis (OR=2.44, p＜0.001) and pericarditis (OR=1.62, p=0.029), had a higher detection rate of anti-double stranded deoxyribonucleic acid (anti-dsDNA antibodies, OR=2.22, p＜0.001), anti-Smith antibodies (anti-Sm antibodies, OR=1.70, p=0.002), low level of complement (OR=1.37, p=0.043) and absence of antiphospholipid antibodies (aPL antibodies, OR=1.60, p=0.002), and had higher wGRS (OR=1.16, p=0.012). Mediation analysis suggested that anti-Sm antibodies and low complement could be mediators in the relationship between high wGRS and the presence of LN. @*Conclusion@#Onset age, pleuritis, pericarditis, several serologic markers, and wGRS were associated with the presence of LN. Anti-Sm antibodies and low complement appeared to mediate the indirect relationship between wGRS and the presence of LN.

Clinical and Genetic Risk Factors Associated With the Presence of Lupus Nephritis

Objective@#To elucidate whether clinical features and the weighted genetic risk score (wGRS) were associated with the presence of lupus nephritis (LN). @*Methods@#We retrospectively divided patients with systemic lupus erythematosus (SLE, n=1,078) into biopsy-proven LN (n=507) and non-LN groups (non-LN, n=571). Baseline clinical features, serologic markers, and the wGRS were collected. The wGRS was calculated from 112 non-human leukocyte antigen (non-HLA) loci and HLA-DRβ1 amino acid haplotypes for SLE. Associations among clinical features, wGRS, and the presence of LN were identified. @*Results@#In the multivariate analysis, patients with LN were younger at diagnosis (odds ratio [OR]=0.97, p＜0.001), had more pleuritis (OR=2.44, p＜0.001) and pericarditis (OR=1.62, p=0.029), had a higher detection rate of anti-double stranded deoxyribonucleic acid (anti-dsDNA antibodies, OR=2.22, p＜0.001), anti-Smith antibodies (anti-Sm antibodies, OR=1.70, p=0.002), low level of complement (OR=1.37, p=0.043) and absence of antiphospholipid antibodies (aPL antibodies, OR=1.60, p=0.002), and had higher wGRS (OR=1.16, p=0.012). Mediation analysis suggested that anti-Sm antibodies and low complement could be mediators in the relationship between high wGRS and the presence of LN. @*Conclusion@#Onset age, pleuritis, pericarditis, several serologic markers, and wGRS were associated with the presence of LN. Anti-Sm antibodies and low complement appeared to mediate the indirect relationship between wGRS and the presence of LN.

Standardized, musculoskeletal ultrasonographic reference values for healthy Korean adults

BACKGROUND/AIMS@#To define standard reference values for musculoskeletal ultrasonography (MSUS) in Korea.@*METHODS@#A total of 251 healthy adults were recruited for this study. Ultrasonography was performed by experienced rheumatologists who had undergone four appropriate training programs in Korea. A General Electric LOGIQ electronic ultrasound device fitted with a 12 MHz linear transducer was employed. Mean values ± standard deviations (SDs) were defined as standard reference values. Intraclass correlation coefficients was employed to evaluate the extent of inter- and intraobserver agreement when MSUS measurements were made.@*RESULTS@#The 251 study participants included 122 males. Mean subject age was 28.6 years. The average bone-to-capsule distance of the right-side second and third metacarpophalangeal (MCP) joints were 0.68 and 0.72 mm respectively, and those of the left-side joints 0.62 and 0.68 mm. The cartilage thicknesses of the right-side second and third MCP joints were 0.55 and 0.55 mm, and those of the left-side joints were 0.55 and 0.56 mm, respectively. The bone-to-capsule distances of the right and left wrists were 0.80 and 0.82 mm. In 12.4% of participants (31/251), the erosion score of the humeral head was 1.71. In the right-side knee joint, mean cartilage thicknesses of the medial and lateral condyles were 1.86 and 2.03 mm in longitudinal scans. High overall interobserver agreement was evident after appropriate training that included instruction on standard MSUS methodology.@*CONCLUSIONS@#We defined standard reference values for MSUS in healthy Korean adults. The reliabilities of interobserver agreements were high after appropriate training program.

Prevalence and Associated Factors for Non-adherence in Patients with Rheumatoid Arthritis

OBJECTIVE: To estimate the prevalence of non-adherence to rheumatoid arthritis (RA) medication and identify the associated factors for non-adherence in RA patients. METHODS: Among the KORean Observational study Network for Arthritis 3,523 patients who completed a questionnaire about the adherence to RA medication were analyzed. The patients were divided into two groups: 1) adherent group, patients who skipped medication ≤5 days within the past 2 months; and 2) non-adherent group, patients who skipped ≥6 days of medication. The baseline characteristics were compared, and multivariable regression analysis was performed to identify the associated factors for non-adherence. RESULTS: The non-adherent group had 339 patients (9.6%). The common causes of non-adherence were forgetfulness (45.8%), absence of RA symptoms (24.7%), and discomfort with RA medication (13.1%). Younger age (odds ratio [OR] 1.02, p < 0.01) and higher income (OR 1.70, p < 0.01) were associated with an increased risk of non-adherence. Whereas higher functional disability (OR 0.68, p < 0.01) and oral corticosteroid use (OR 0.73, p=0.02) were associated with a decreased risk of non-adherence. The associated factors differed according to cause of non-adherence. Having adverse events (OR 2.65, p=0.02) was associated with the risk of non-adherence due to discomfort with RA medication while a higher level of education (OR 2.37, p=0.03) was associated with the risk of non-adherence due to an absence of RA symptoms. CONCLUSION: The 9.6% of Korean RA patients were non-adherent to RA medication. The associated factors differed according to the cause of non-adherence. Therefore, an individualized approach will be needed to improve the adherence to RA medication.

Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Diagnosis and Assessment of Takayasu Arteritis and Ulcerative Colitis

Takayasu arteritis (TA) and ulcerative colitis (UC), both immune-mediated inflammatory diseases, rarely occur together. This report describes TA in a 29-year old female patient who was being treated for UC for three years. As she had left-side neck pain and headache, she was diagnosed with TA and her response to tumor necrosis factor (TNF) inhibitor was assessed by fluorine-18-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET)/computed tomography (CT). Positive responses to the TNF inhibitor were seen by PET/CT for the TA and by endoscopy for the UC. We conclude that TNF inhibitors are effective treatments for both TA and UC. We found that PET/CT is a useful for diagnosing and assessing TA.

ABCG2 Polymorphism Is Associated with Hyperuricemia in a Study of a Community-Based Korean Cohort

The purpose of the present study was to find novel loci associated with hyperuricemia using data from a genome-wide association study (GWAS) conducted on healthy Koreans. We conducted a GWAS using data from a community-based cohort study where 3,647 subjects aged 40–89 were recruited by the Korea National Institute of Health (KNIH). The community-based cohort consisted of subjects who did not suffer from any of 6 major diseases (hypertension, hyperlipidemia, diabetes, heart diseases, brain diseases, and cancers). Epidemiologic information includes 249 traits such as epidemiological surveys, physical examinations, and laboratory tests. A total of 3,647 participants, including 234 hyperuricemia cases (serum uric acid [SUA] level was 7 mg/dL or higher) and 3,413 controls, were genotyped by Illumina HumanOmni1-Quad BeadChip GWAS array at KNIH. In the multivariate regression analysis of clinical variables, significant variables associated with hyperuricemia were male gender (odds ratio [OR], 5.526; P = 3.2 × 10⁻¹⁰), old age (OR, 1.017; P = 0.040), high body mass index (BMI) (OR, 1.147; P = 5.4 × 10⁻⁷), current alcohol intake (OR, 2.413; P = 4.7 × 10⁻⁷), and high creatinine (OR, 1.647; P = 1.6 × 10⁻¹³). We identified a hyperuricemia susceptible loci (rs2054576 in ABCG2, OR, 1.883; P = 4.7 × 10⁻⁸) that passed a genome-wide significance threshold, adjusted by clinical variables (male, age, BMI, current alcohol, and creatinine). It was first identified that rs2054576 in ABCG2 is associated with hyperuricemia. Our results should be validated through replication studies among other Korean subjects or various ethnic groups.

Impact of early diagnosis on functional disability in rheumatoid arthritis

BACKGROUND/AIMS: To determine whether early diagnosis is beneficial for functional status of various disease durations in rheumatoid arthritis (RA) patients. METHODS: A total of 4,540 RA patients were enrolled as part of the Korean Observational Study Network for Arthritis (KORONA). We defined early diagnosis as a lag time between symptom onset and RA diagnosis of ≤ 12 months, whereas patients with a longer lag time comprised the delayed diagnosis group. Demographic characteristics and outcomes were compared between early and delayed diagnosis groups. Logistic regression analyses were performed to identify the impact of early diagnosis on the development of functional disability in RA patients. RESULTS: A total of 2,597 patients (57.2%) were included in the early diagnosis group. The average Health Assessment Questionnaire-Disability Index (HAQ-DI) score was higher in the delayed diagnosis group (0.64 ± 0.63 vs. 0.70 ± 0.66, p < 0.01), and the proportion of patients with no functional disability (HAQ = 0) was higher in the early diagnosis group (22.9% vs. 20.0%, p = 0.02). In multivariable analyses, early diagnosis was independently associated with no functional disability (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.01 to 1.40). In a subgroup analysis according to disease duration, early diagnosis was associated with no functional disability in patients with disease duration < 5 years (OR, 1.37; 95% CI, 1.09 to 1.72) but not in patients with longer disease duration (for 5 to 10 years: OR, 1.07; 95% CI, 0.75 to 1.52; for ≥ 10 years: OR, 0.92; 95% CI, 0.65 to 1.28). CONCLUSIONS: Early diagnosis is associated with no functional disability, especially in patients with shorter disease duration.

Impact of Childbearing Decisions on Family Size of Korean Women with Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) predominantly affects women in their reproductive years and has a significant impact on childbearing. We investigated the influence of personal decision on family size among Korean women with SLE and factors that affect the decisions. A case-control study comparing childbearing history and decisions of 112 SLE patients and 135 controls was performed. Women with SLE participating in the Network for Lupus Clinical Research in South Korea and matching controls between ages of 18-45, who are/were married or living with a partner were included. Data regarding socio-demographics, reproductive history, and childbearing decisions were collected through a survey using a standardized questionnaire and medical record review. More women with SLE reported at least one pregnancy (85.7% vs. 71.9%, P = 0.009) or at least one live birth (85.7% vs. 71.9%, P = 0.003) compared with controls. Mean number of pregnancies was significantly higher (2.4 ± 1.6 vs. 1.4 ± 1.3, P < 0.001), and mean number of live births was significantly lower in women with SLE (1.2 ± 0.8 vs. 1.6 ± 0.8, P < 0.001). Significantly more women with SLE made the decision not to have children compared with controls (54.5% vs. 40.7%, P = 0.031), and health-related concerns were the major cause of the decision. Other socio-demographic factors did not influence the decision to limit childbearing in SLE women. The disease-related concerns had significant impact on family size and childbearing decisions among Korean women with SLE.

A Case of Ischiofemoral Impingement Syndrome as a Differential Diagnosis of Ankylosing Spondylitis

Ischiofemoral impingement (IFI) syndrome is an uncommon cause of gluteal and hip pain. We report on a case of a 20-year-old man who presented with chronic gluteal and hip pain with low back pain without a history of trauma or surgery. He was misdiagnosed with ankylosing spondylitis (AS) at another clinic. The patient was finally diagnosed with IFI syndrome according to pelvic magnetic resonance imaging findings at our hospital. After two weeks of medical and physical treatment, his pain showed gradual improvement. Because IFI syndrome is rarely reported in male patients, it might be misdiagnosed as AS. Therefore, IFI syndrome should be considered as a differential diagnosis of AS, particularly in young male patients with atypical pain characteristics.

A Case of Pachydermoperiostosis Combined with Undifferentiated Arthritis

Pachydermoperiostosis (PDP) is a primary hypertrophic osteoarthropathy characterized by digital clubbing, pachydermia, and periostosis, which is inherited as an autosomal dominant or recessive trait. We report on a patient suffering from bilateral knee arthritis for 6 years who was newly diagnosed as PDP. PDP was confirmed by bilateral digital clubbing, hyperhidrosis, and cutis verticis gyrata, findings of pachydermatosis on the forehead and scalp, X-ray findings of proliferative periostitis. This case indicates that PDP is one of several possible rare diseases that should be considered in patients with undifferentiated arthritis.

Diffuse Skeletal Hemangiomatosis Mimicking Sacroiliitis

Hemangiomatosis of the skeletal system is a rare disease without specific symptoms and signs. We describe a 20-year-old patient with low back pain, whose plain radiographs of sacroiliac (SI) joint showed irregular sclerotic lesions. The patient was finally confirmed with skeletal hemangiomatosis by magnetic resonance imaging (MRI) and excisional biopsy of the lesion. The present case suggests that if patients with abnormal lesions of the SI joint in the plain radiographs do not have typical inflammatory back pain, advanced imaging is required to make an accurate diagnosis. Our case also emphasizes the importance of MRI and biopsy in establishing the diagnosis.

Prediction for TNF Inhibitor Users in RA Patients According to Reimbursement Criteria Based on DAS28

OBJECTIVE: The purpose of this study is to examine the difference between the numbers of patients in rheumatoid arthritis (RA) who are eligible to TNF inhibitors by the past Korean National Health Insurance reimbursement guideline and by the disease activity score with 28-joint assessment (DAS28) based criteria. METHODS: Data were obtained from a multi-center registry for biologics users in Korean RA patients, BIOlogics Pharmacoepidemiologic StudY (BIOPSY). DAS28 was calculated based on either ESR or CRP, and DAS28 of more than 5.1 or between 3.2 and 5.1 with radiographic changes was defined as a cut-off point for the initiation of TNF inhibitors. For the maintenance criteria, we used both of improving in DAS28 score (>1.2) and low disease activity (DAS 28<3.2). Differences between the numbers in each step by two criteria were described with Chi-square test and Kappa agreement. RESULTS: Of the 489 patients in BIOPSY, 299 were included in this study. Among them, 278 patients (93.0%) were eligible of TNF inhibitors when we applied the new initiation criteria with DAS28-ESR, and 244 patients (81.6%) were indicated for TNF inhibitors with DAS28-CRP. For the maintenance criteria, a low disease activity (DAS28<3.2) in 3 months after starting TNF inhibitors is too strict for achieving (33.6% with DAS28-ESR and 50.0% with DAS28-CRP). Instead, decreasing DAS28 by more than 1.2 is more reasonable as a tool for deciding early responsiveness of TNF inhibitors in RA patients (81.2% both with DAS28-ESR and DAS28-CRP). CONCLUSION: Our results show that the candidates for TNF inhibitors will be enormously changed according to a change in the reimbursement criteria. To define appropriate patients to receive TNF inhibitors, a further study with regard to the impact of changes in the reimbursement criteria on the outcomes of RA patients will be required.

Caspase-1 Level in Synovial Fluid Is High in Patients with Spondyloarthropathy but Not in Patients with Gout

Activation of caspase-1 by NALP3 inflammasomes has been shown to be important in initiating acute gouty arthritis. The objectives of this study were to measure the levels of caspase-1 in synovial fluid in gout and various arthritides, and to elucidate the clinical significance of caspase-1 levels in synovial fluid. Caspase-1, IL-1beta, IL-18, and uric acid were measured in synovial fluid from 112 patients with gout and other arthritides, such as rheumatoid arthritis, osteoarthritis, and spondyloarthropathy. Caspase-1 in synovial fluid from patients with crystal-induced arthritis, inflammatory arthritis, osteoarthritis, and spondyloarthropathy was 35.9 +/- 86.7, 49.7 +/- 107.7, 2.1 +/- 7.0, and 152.6 +/- 155.7 pg/mL, respectively. The mean level and the frequency of high levels (> or =125 pg/mL) of caspase-1 in spondyloarthropathy were significantly higher than those in the other arthritides including gout. Caspase-1 was detectible in the synovial fluid of patients with the various arthritides. Contrary to our hypothesis, the caspase-1 level in the synovial fluid of patients with gout was not higher than in that of other arthritides. High levels of caspase-1 may be helpful in differentiating spondyloarthropathy from other arthritides.

A Case of Klinefelter's Syndrome Accompanying with Polymyositis

Klinefelter's syndrome which is characterized by hypogonadism with karyotype abnormality (47 XXY or 46 XY/47 XXY) in males has been reported to be associated with autoimmune diseases including rheumatoid arthritis and systemic lupus erythematosus. However, Klinefelter's syndrome accompanying with polymyositis has rarely been reported. We report a case of KFS with polymyosits in a 38-year old man for the first time in Korea.

A Case of Peritoneal Tuberculosis Developed after Infliximab Therapy for Refractory RA / 결핵및호흡기질환

Recently, interferon gamma releasing assay has been recommended to compensate the tuberculin skin test (TST) for screening for latent tuberculosis infection (LTBI). Although it improved the detection of LTBI before treatment with tumor necrosis factor blocker, its application to immune suppressed patients is limited. We report a case of peritoneal tuberculosis (TB) developed in a patient who tested positive for TST and QuantiFERON-TB Gold (QFT-G) before infliximab therapy, to emphasize the importance of monitoring during treatment. A 52-year-old woman presented with abdominal distension. She had been diagnosed with seropositive rheumatoid arthritis six years ago. She had started taking infliximab six months ago. All screening tests for TB were performed and the results of all were negative. At admission, the results of repeated TST and QFT-G tests were positive. Histopathological examination confirmed peritoneal TB. The patient started anti-TB therapy and the symptoms were relieved.

A Case of Ankylosing Spondylitis with Spinal Metastasis of Cholangiocarcinoma / 대한류마티스학회지

Back pain is the most common symptom of ankylosing spondylitis (AS). The aggravation of back pain in AS patients is usually thought to be a flare-up of the disease activity. We report here on the case of a 31-year-old AS patient with low back pain. The lesions of this patient were unexpectedly diagnosed as metastatic spinal tumor due to cholangiocarcinoma. In a patient with AS, an acute aggravation of low back pain may be due to other pathologic conditions such as osteoporotic vertebral fracture, vertebral discitis and metastatic bone disease. Therefore, when a patient with AS presents with nonspecific low back pain, a physician should consider the above mentioned conditions.

Treatment of Late Onset Ankylosing Spondylitis with TNF Antagonist: A Case Series / 대한류마티스학회지

Ankylosing spondylitis is a disease that shows a young age of onset (less than 40 years old), inflammatory back pain, sacroiliitis and a strong association with HLA-B27. Yet some recently reported cases have presented with a late age of onset (more than 55 years old), atypical clinical presentations and a low response to NSAIDs, and this has also been named late onset spondyloarthropathy (LOSPA). As compared with early onset spondyloarthropathy (EOSPA), the LOSPA patients more frequently suffer with combined peripheral arthritis and inflammatory systemic symptoms and a high ESR and CRP level, but they lack the typical axial symptoms. Yet there have been few reports about late onset ankylosing spondylitis (LOAS). The previous cases of LOSPA and LOAS were managed with NSAIDs, steroids, methotrexate and sulfasalazine, but none were managed with TNF antagonists. LOAS is rare and difficult for management because of the patients' older age and the lack of experiences with this malady, so we report here on the four cases of LOAS that were successfully treated by TNF antagonists.

A Case of the Lumbar Spine Involvement and Sacroiliitis in a Patient with Gout / 대한류마티스학회지

Although gout often initially affects the peripheral joints, gout may also involve the axial joints. The radiologic changes of axial gout are more common than are clinically recognized. According to a recent report, when the spine CT images of peripheral gout were reviewed for features of axial gout, there was about a 14% frequency of suspected axial gout. The vertebral level and the finding with the most common spinal gouty changes were L4 and lumbar facet joint erosions. We describe here the case of a 36-year-old gout patient with low back and right buttock pain and his lesions were unexpectedly diagnostic of lumbar facet joint arthritis and right sacroiliitis.

A Case of IgA Nephropathy Associated with Systemic Lupus Erythematosus / 대한류마티스학회지

Renal involvement is frequently seen in patients with systemic lupus erythematosus (SLE). The occurrence of non-lupus nephritis, and especially IgA nephropathy, in SLE patients has rarely been reported. We describe here the case of a 30-year-old woman who had systemic lupus erythematosus and nontuberculous mycobacterial lung disease, and her biopsy of a renal lesion was unexpectedly diagnostic of IgA nephropathy. Although both IgA nephropathy and lupus nephritis are immune complex mediated diseases, their laboratory and histopathologic findings and the extra-renal clinical manifestations are different and these all support a different pathogenesis for the 2 diseases. Renal biopsy plays a crucial role in identifying and diagnosing renal lesions, which may have prognostic and therapeutic implications that are distinct from those of lupus nephritis. In conclusion, performing a renal biopsy in SLE patients who have urinary abnormalities is important since a correct diagnosis would permit the most appropriate treatment to be started and so avoid unnecessary immunosuppressive treatments.