Association between Allergic Diseases and the Number of Persons per Household Using Data from the National Health and Nutrition Examination Survey / 대한피부과학회지

Background@#Atopic dermatitis (AD) and asthma are chronic allergic diseases that affect quality of life. @*Objective@#In this study, we analyzed data from the Korea National Health and Nutrition Examination Survey (KNHANES) to determine the association between allergic diseases and number of household members living with the patient. @*Methods@#This study included 20,893 participants ＞19 years of age from the KNHANES (2010∼2013). Multiple logistic regression analysis was performed to evaluate the odds ratio (OR) for presence of AD or asthma according to number of household members. @*Results@#The OR of allergic diseases including AD and/or asthma increased as the number of household members decreased in the age ＜40 group after adjustments for age, sex, smoking status, drinking status, regular physical activity, education level, income level, and stress level (1 member: adjusted OR [aOR]=2.019, 95% confidence interval [CI]=1.256∼3.245; 2 or 3 members: aOR=1.3, 95% CI=1.031∼1.64; ≥4 members: reference). And those with an allergic disease were less likely to have a spouse and had a higher stress level compared to those without. @*Conclusion@#Based on a nationwide population-based survey, this study showed that the number of household members was significantly related to rates of AD and asthma. The prevalence of allergic diseases tended to be higher in households with fewer members.

Perspectives on single-nucleus RNA sequencing in different cell types and tissues

Single-cell RNA sequencing has become a powerful and essential tool for delineating cellular diversity in normal tissues and alterations in disease states. For certain cell types and conditions, there are difficulties in isolating intact cells for transcriptome profiling due to their fragility, large size, tight interconnections, and other factors. Single-nucleus RNA sequencing (snRNA-seq) is an alternative or complementary approach for cells that are difficult to isolate. In this review, we will provide an overview of the experimental and analysis steps of snRNA-seq to understand the methods and characteristics of general and tissue-specific snRNA-seq data. Knowing the advantages and limitations of snRNA-seq will increase its use and improve the biological interpretation of the data generated using this technique.

A Case Report of Pirfenidone-Induced Lichenoid Drug Eruption in a Patient with Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and lethal lung disease characterized by progressive dyspnea and irreversible loss of lung function. Pirfenidone is a novel anti-fibrotic and anti-inflammatory drug, which reduces deterioration in the lung function and prolongs progression-free survival in patients with IPF. However, ithas adverse effects including gastrointestinal symptoms, hepatic dysfunction or skin photosensitivity, and rash. Lichenoid drug eruption (LDE) refers to lichen planuslike drug eruption usually presenting symmetric eczematous plaques with a purple hue. To date, numerous cases of LDE due to various drugs and pirfenidone-associated photosensitivity have been reported. However, a case of pirfenidone-induced LDE has been very rarely reported to our knowledge. Herein, is a case of pirfenidone-induced LDE so that clinicians can be aware of the possibility of LDE when using pirfenidone.

A Case of Newly Developed Pemphigus Foliaceus and Possible Association with Alternative Bee-Venom Therapy

Bee-venom is composed of a variety of peptides, enzymes, and biogenic amines, and is demonstrated to have both anti-inflammatory and immune-stimulatory effects in human body. Pemphigus foliaceus (PF) is a variant of pemphigus, which is a rare autoimmune bullous disease presenting with erythematous scaly crusted plaques. Although the exact pathogenesis was not identified, there have been three case reports of autoimmune disorders associated with bee-venom. In this case, a 64-year-old female was diagnosed with PF, which was developed after alternative bee-venom acupuncture therapy. We assumed that the bee-venom caused the diseases through a temporal relationship and its known immunostimulatory action. Herein, we suggest that physicians recognize the possibility of bee-venom stimulating the immune system and triggering various autoimmune diseases including pemphigus.

A Case of Newly Developed Pemphigus Foliaceus and Possible Association with Alternative Bee-Venom Therapy

Bee-venom is composed of a variety of peptides, enzymes, and biogenic amines, and is demonstrated to have both anti-inflammatory and immune-stimulatory effects in human body. Pemphigus foliaceus (PF) is a variant of pemphigus, which is a rare autoimmune bullous disease presenting with erythematous scaly crusted plaques. Although the exact pathogenesis was not identified, there have been three case reports of autoimmune disorders associated with bee-venom. In this case, a 64-year-old female was diagnosed with PF, which was developed after alternative bee-venom acupuncture therapy. We assumed that the bee-venom caused the diseases through a temporal relationship and its known immunostimulatory action. Herein, we suggest that physicians recognize the possibility of bee-venom stimulating the immune system and triggering various autoimmune diseases including pemphigus.

Effect of Oral Alitretinoin Therapy on Trachyonychia / 대한피부과학회지

Background@#Trachyonychia is a condition characterized by longitudinal ridging, pitting, and roughness of the nail surface. It tends to be resistant to various treatment modalities, often leading to a clinically unsatisfactory outcome. Alitretinoin (9-cis-retinoic acid; Alitoc Capsule) is approved for patients with severe chronic hand eczema and has been shown to be effective for other skin diseases. However, only few studies have demonstrated the efficacy of oral alitretinoin for the treatment of trachyonychia. @*Objective@#We aimed to evaluate the efficacy and safety of oral alitretinoin therapy for the treatment of trachyonychia. @*Methods@#We reviewed the medical records and clinical photographs of patients with trachyonychia who were treated with oral alitretinoin therapy between January 2016 and December 2019 in the Department of Dermatology of Yeouido St. Mary’s Hospital. Photographs of the lesions were taken and evaluated at 0, 1, 3, 6, and 12 months. The severity of trachyonychia was assessed into 5 grades according to the roughness of the nail and the distribution of affected areas. @*Results@#Thirty patients (male: 12, female: 18) with a mean age of 51.5±11.1 years were included in the study. After treatment with oral alitretinoin at a dosage of 10∼30 mg/day, the severity of trachyonychia tended to decrease as the number of treatment sessions increased. The mean treatment duration was 6.9±4.1 months. The therapeutic effects were as follows. After 3 months of treatment, 88.0% of the patients showed partial remission, and all the patients showed improvement after ＞6 months of treatment. After 12 months of treatment, 20.0% of the patients achieved complete remission. @*Conclusion@#Oral alitretinoin therapy may be an effective and safe treatment option for trachyonychia.

A Case of Lepromatous Leprosy in an Elderly Patient / 대한피부과학회지

Leprosy is an infectious disease caused by Mycobacterium leprae. Patients usually present with hypopigmented or erythematous plaques with central hypoesthesia or tenderness, and necessitate a differential diagnosis with eczema, granuloma annulare, sarcoidosis, syphilid, mycosis fungoides, erythema nodosum, and skin cancer. A 93-year-old woman presented with asymptomatic erythematous plaques and subdermal nodules on the face and extremities for 6∼ 7 months, and the lesions were suspicious for skin cancer. Histopathologic examination revealed diffuse infiltration of foamy histiocytes separated by a grenz zone. Acid-fast bacilli were seen in Ziehl−Neelsen stain with clumps called globi. Based on clinical and histopathological findings, she was finally diagnosed with lepromatous leprosy.The patient was diagnosed with leprosy at an advanced age; thus, we report the case in which dermatologists should consider leprosy as well as skin cancer in the elderly patients with unusual erythematous nodules, despite decreasing prevalence of leprosy.

Distinct Urinary Metabolic Profile in Rheumatoid Arthritis Patients: A Possible Link between Diet and Arthritis Phenotype

OBJECTIVE: We undertook this study to investigate the discriminant metabolites in urine from patients with established rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and from healthy individuals. METHODS: Urine samples were collected from 148 RA patients, 41 SLE patients and 104 healthy participants. The urinary metabolomic profiles were assessed using 1H nuclear magnetic resonance spectroscopy. The relationships between discriminant metabolites and clinical variables were assessed. Collagen-induced arthritis was induced in mice to determine if a choline-rich diet reduces arthritis progression. RESULTS: The urinary metabolic fingerprint of patients with established RA differs from that of healthy controls and SLE patients. Markers of altered gut microbiota (trimethylamine-N-oxide, TMAO), and oxidative stress (dimethylamine) were upregulated in patients with RA. In contrast, markers of mitochondrial dysfunction (citrate and succinate) and metabolic waste products (p-cresol sulfate, p-CS) were downregulated in patients with RA. TMAO and dimethylamine were negatively associated with serum inflammatory markers in RA patients. In particular, patients with lower p-CS levels exhibited a more rapid radiographic progression over two years than did those with higher p-CS levels. The in vivo functional study demonstrated that mice fed with 1% choline, a source of TMAO experienced a less severe form of collagen-induced arthritis than did those fed a control diet. CONCLUSION: Patients with RA showed a distinct urinary metabolomics pattern. Urinary metabolites can reflect a pattern indicative of inflammation and accelerated radiographic progression of RA. A choline-rich diet reduces experimentally-induced arthritis. This finding suggests that the interaction between diet and the intestinal microbiota contributes to the RA phenotype.

MicroRNA-143 and -145 modulate the phenotype of synovial fibroblasts in rheumatoid arthritis

Fibroblast-like synoviocytes (FLSs) constitute a major cell subset of rheumatoid arthritis (RA) synovia. Dysregulation of microRNAs (miRNAs) has been implicated in activation and proliferation of RA-FLSs. However, the functional association of various miRNAs with their targets that are characteristic of the RA-FLS phenotype has not been globally elucidated. In this study, we performed microarray analyses of miRNAs and mRNAs in RA-FLSs and osteoarthritis FLSs (OA-FLSs), simultaneously, to validate how dysregulated miRNAs may be associated with the RA-FLS phenotype. Global miRNA profiling revealed that miR-143 and miR-145 were differentially upregulated in RA-FLSs compared to OA-FLSs. miR-143 and miR-145 were highly expressed in independent RA-FLSs. The miRNA-target prediction and network model of the predicted targets identified insulin-like growth factor binding protein 5 (IGFBP5) and semaphorin 3A (SEMA3A) as potential target genes downregulated by miR-143 and miR-145, respectively. IGFBP5 level was inversely correlated with miR-143 expression, and its deficiency rendered RA-FLSs more sensitive to TNFα stimulation, promoting IL-6 production and NF-κB activity. Moreover, SEMA3A was a direct target of miR-145, as determined by a luciferase reporter assay, antagonizing VEGF165-induced increases in the survival, migration and invasion of RA-FLSs. Taken together, our data suggest that enhanced expression of miR-143 and miR-145 renders RA-FLSs susceptible to TNFα and VEGF165 stimuli by downregulating IGFBP5 and SEMA3A, respectively, and that these miRNAs could be therapeutic targets.

Identification of novel urinary biomarkers for assessing disease activity and prognosis of rheumatoid arthritis

To optimize treatment for rheumatoid arthritis (RA), it is ideal to monitor the disease activity on a daily basis because RA activity fluctuates over time. Urine can be collected routinely at home by patients. Recently, we identified four urinary biomarker candidates—gelsolin (GSN), orosomucoid (ORM)1, ORM2 and soluble CD14 (sCD14)—in RA patients through transcriptomic and proteomic studies. Here, we investigated the clinical significance of the aforementioned urinary biomarker candidates in a prospective manner. For the first time, we found that urinary ORM1, ORM2 and sCD14 levels, but not GSN, were elevated in RA patients and had a positive correlation with the status of the disease activity. In particular, urine tests for ORM 1, ORM 2 and sCD14 efficiently represented the presence of high RA activity without the need for measuring blood markers. In a parallel study, a more rapid radiographic progression over 3 years was observed in patients with higher ORM2 levels. Combined measurements of urinary ORM2 and serum C-reactive protein synergistically increased the predictability of the radiographic progression of RA (odds ratio: 46.5). Collectively, our data provide evidence that blood-free, urinary biomarkers are promising surrogates for assessing disease activity and prognosis of RA. We anticipate that our urinary biomarkers will provide novel candidates for patient-driven measurements of RA activity at home and can shift the paradigm from blood to urine testing in the assessment of RA activity and prognosis in hospitals.

Role of Endoplasmic Reticulum Stress in Rheumatoid Arthritis Pathogenesis

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by abnormal proliferation of synoviocytes, leukocyte infiltration, and angiogenesis. The endoplasmic reticulum (ER) is the site of biosynthesis for all secreted and membrane proteins. The accumulation of unfolded proteins in the ER leads to a condition known as ER stress. Failure of the ER's adaptive capacity results in abnormal activation of the unfolded protein response. Recently, we have demonstrated that ER stress-associated gene signatures are highly expressed in RA synovium and synovial cells. Mice with Grp78 haploinsufficiency exhibit the suppression of experimentally induced arthritis, suggesting that the ER chaperone GRP78 is crucial for RA pathogenesis. Moreover, increasing evidence has suggested that GRP78 participates in antibody generation, T cell proliferation, and pro-inflammatory cytokine production, and is therefore one of the potential therapeutic targets for RA. In this review, we discuss the putative, pathophysiological roles of ER stress and GRP78 in RA pathogenesis.

Expression and Function of Calcineurin in Inflammatory Arthritis

BACKGROUND: Calcineurin plays a crucial role in T cell activation, cell growth, apoptosis, and angiogenesis, and its over-expression has been implicated in the pathogenesis of cardiomyopathy and stroke. However, the expression and function of calcineurin in the pathologic lesion of chronic inflammatory diseases, like rheumatoid synovium, remain to be defined. This study was aimed to determine the role of calcineurin in inflammatory arthritis and investigate the expression and function of calcineurin in the rheumatoid synovium and synoviocytes, the actual site of chronic inflammation. METHODS: Immunohistochemical staining using specific antibody to calcineurin was perfomed in the synovium of rheumatoid arthritis (RA). Fibroblast-like synoviocytes (FLS) from RA and osteoarthritis (OA) patients were isolated from RA and OA patients, and cultured with IL-1beta and TNF-alpha in the presence or absence of cyclosporin A, a calcineurin inhibitor. The calcineurin expression was assessed by phosphatase assay and Western blotting analysis. IL-6, -10, -17, matrix metalloproteinase (MMP)-1, -2, -3, and -9 released into the culture supernatants were measured by ELISA. After transfection with GFP-Cabin 1 gene into synoviocytes, the levels of IL-6 and MMPs were measured by ELISA. RESULTS: Calcineurin was highly expressed in the lining layer of synovium and cultured synoviocytes of RA patients. The elevated calcineurin activity in the rheumatoid synoviocytes was triggered by proinflammatory cytokines such as IL-1beta and TNF-alpha. In contrast, IL-10, an anti-inflammatory cytokine, failed to increase the calcineurin activity. The targeted inhibition of calcineurin by the over-expression of Cabin 1, a natural calcineurin antagonist, inhibited the production of IL-6 and MMP-2 by rheumatoid synoviocytes in a similar manner to the calcineurin inhibitor, cyclosporin A. CONCLUSION: These data suggest that abnormal activation of calcineurin in the synoviocytes may contribute to the pathogenesis of chronic arthritis, and thus provide a potential target for controlling inflammatory arthritis.

Elevated Serum Osteoprotegerin Levels in Systemic Lupus Erythematosus / 대한류마티스학회지

OBJECTIVE: To determine the serum levels of soluble osteoprotegerin (OPG), decoy receptor of receptor activator of nuclear factor kB ligand (RANKL), in patients with systemic lupus erythematosus (SLE) and to assess the its relationships with certain clinical manifestations. METHODS: Serum levels of OPG in 60 patients with SLE and 30 healthy controls were determined by enzyme-linked immunosorbent assay. At the time of serum sampling, clinical manifestations and lupus disease activity index (SLEDAI) were assessed. RESULTS: Serum levels of OPG in 60 patients with SLE were significantly higher than in 30 healthy controls (1,058+/-699 versus 806+/-113 pg/mL, p=0.008). Patients with active disease had higher levels of OPG levels than those with inactive disease (1,355+/-837 versus 760+/-113 pg/mL, p<0.001). Serum OPG levels correlated with SLEDAI (gamma=0.588, p<0.0001), anti-dsDNA antibody titers (gamma=0.337, p=0.009) and serum MCP-1 levels (gamma=0.485, p<0.0001). In particular, serum OPG levels were found to be significantly increased in patients with neurological manifestation compared to those without (1,504+/-1,152 versus 918+/-376 pg/mL, p=0.004). CONCLUSION: The results of this study suggest that serum OPG levels are increased in patients with SLE. Serum OPG has a role as marker for disease activity and its increased levels reflect the involvement of neurological manifestation.

Effect and Mechanism of Arginine-rich Anti-vascular Endothelial Growth Factor Hexapeptide, RRKRRR, on the Regulation of Rheumatoid Inflammation / 대한류마티스학회지

OBJECTIVE: Vascular endothelial growth factor (VEGF) has been suggested to play a critical role in the pathogenesis of rheumatoid arthritis (RA). It has been demonstrated that synthetic arginine-rich hexapeptide, RRKRRR, shows significant inhibition of VEGF-induced angiogenesis, and also retarded the growth and metastasis of colon carcinoma cell by blocking the interaction between VEGF and its receptor. In this study, we investigated whether anti-VEGF RRKRRR peptide (dRK6) could regulate the activation of mononuclear cells of RA patients and suppress collagen-induced arthritis (CIA) in mice. METHODS: Synovial fluid mononuclear cells (SFMC) or synoviocytes from RA patients were cultured in the presence of VEGF, and the levels of TNF-alpha and IL-6 were determined in the culture supernatants by ELISA. Blocking experiments were performed by adding dRK6 to thecells stimulated with VEGF. Additionally, the in vivo effect of dRK6 on the development of arthritis was tested in collagen induced arthritis (CIA) in DBA/1 mice. T cell responses to type II collagen (CII) and IgG antibodies to CII were examined in draining lymph node cells and sera of the mice, respectively. RESUTLS: dRK6 showed concentration-dependent inhibitory activity for the VEGF binding to its receptor on human vascular endothelial cells. The treatment of dRK6 completely abrogated the VEGF-induced productions of TNF-alpha and IL-6 by RA SFMC or synoviocytes. Moreover, a subcutaneous injection of dRK6 resulted in a dose-dependent decrease in the severity and incidence of CIA in mice. In these mice, the T cell responses to type II collagen (CII) in lymph node cells and circulating IgG antibodies to CII were also dose-dependently inhibited by the peptides. CONCLUSION: We observed firstly that anti-VEGF dRK6 blocked the VEGF-induced production of pro-inflammatory cytokine from RA SFMC and synoviocytes, and suppressed the ongoing paw inflammation in mice. These data suggest that dRK6 may be an effective strategy in the treatment of RA, and could be applied to modulate various chronic VEGF-dependent inflammatory diseases.

Hypoxia Induces the Expression of Connective Tissue Growth Factor in Dermal Fibroblasts / 대한류마티스학회지

OBJECTIVE: Connective tissue growth factor (CTGF) has been proposed to play a role in fibrotic process of systemic sclerosis. Since hypoxia was known to be associated with fibrosis in several profibrogenic conditions, we investigated whether CTGF expression in dermal fibroblast is regulated by hypoxia caused by microvascular loss. METHODS: Dermal fribroblasts from patient with systemic sclerosis and normal controls were cultured in the presence of cobalt chloride (CoCl2), a chemical inducer of HIF-1alpha or hypoxic culture conditions. Expression of HIF-1alpha, VEGF and CTGF was evaluated by semiquantitative reverse transcription-polymerase chain reaction and Western blotting. RESULTS: Scleroderma fibroblasts expressed increased levels of HIF-1alpha, VEGF and CTGF compared to normal dermal fibroblasts. Dermal fibroblasts exposed to various concentration of CoCl2 (1~100microM) enhanced the expression of CTGF mRNA in dose-dependent fashion. Actinomycin D significantly blocked the hypoxia-mediated up-regulation of CTGF mRNA expression, whereas cycloheximide did not block the up-regulation. Up-regulation of CTGF by hypoxia was not mediated by endogenous production of transforming growth factor (TGF)-beta. In time-kinetics study, dermal fibroblasts from scleroderma patients exhibited earlier peak expression of CTGF mRNA than those from normal dermal fibroblasts. In addition, simultaneous treatment of suboptimal concentration of CoCl2 and TGF-beta exhibited the up-regulation of CTGF mRNA in additive fashion. Interferon-gamma did not modulate the expression of CTGF mRNA induced by CoCl2, while the up-regulation of CTGF by TGF-beta was downregulated by Interferon-gamma in a dose-dependent fashion. CONCLUSION: These data indicate that hypoxia up-regulates the expression of CTGF in dermal fibroblasts and provide the evidence that hypoxia caused by microvascular alterations contributes the progression of fibrosis in systemic sclerosis by up-regulation of CTGF.

Correlation between Sonographic Severity and Biochemical Markers of Synovium and Cartilage in Knee Osteoarthritis Patients / 대한류마티스학회지

OBJECTIVE: Ultrasonography has benefit in detecting soft tissue abnormalities within the joints, which cannot be assessed by conventional X-ray. In this study, we investigated the relationship between soft tissue and/or bony abnormalities on ultrasonography and biochemical markers of synovium and cartilage in knee osteoarthritis (OA) patients METHODS: Fifty-one knee OA patients who fulfilled the ACR criteria were enrolled in this study. Knee ultrasonography was performed in affected knee joints with a 12 MHz linear probe to assess the presence of effusion, synovial proliferation, capsular distension, length of osteophytes, and thickness of cartilage. At the same time, the serum levels of hyaluronic acid (HA) and cartilage oligomeric protein (COMP) were measured by ELISA and serum osteocalcin levels were determined by RIA. RESULTS: The patients with longer medial osteophytes showed higher levels of serum HA and COMP than those with shorter ones. Serum HA levels were significantly higher in patients with larger amount of effusion and/or synovial proliferation, suggesting inflammatory changes within the joint, than those without. In addition, the severity of capsular distention was also correlated well with serum HA and COMP levels. However, the length of lateral osteophytes and thickness of femoral cartilage were not correlated with serum HA or COMP levels. Serum osteocalcin levels did not show any association with above ultrasonographic parameters, either. CONCLUSIONS: Using knee ultrasonography, we demonstrated that serum HA and COMP levels were elevated in more severe OA patients than less severe patients. This result suggests that detailed pathologic changes in the soft tissue and/or bone of OA joints on ultrasonography are being directly reflected to biochemical markers measured in the peripheral blood.

Vascular Endothelial Growth Factor Stimulates Productions of Tumor Necrosis Factor-alpha and Interleukin-6 from Mononuclear Cells and Synoviocytes of Rheumatoid Arthritis Patients / 대한류마티스학회지

OBJECTIVE: Vascular endothelial growth factor (VEGF), an angiogenic factor, has been suggested to play a critical role in the pathogenesis of rheumatoid arthritis (RA). In this study, we investigated whether VEGF would directly regulate the activation of mononuclear cells of RA patients. MEHTODS: Mononuclear cells and/or synoviocytes of RA patients were cultured in the presence of VEGF, and the levels of TNF-alpha and IL-6 were determined in the culture supernatants by ELISA. The TNF-alpha-or IL-6-producing cells were also assessed by flow cytometry analysis. Blocking experiments were performed by adding anti-VEGF receptor (anti-Flt-1) mAb to the cells, stimulated with VEGF. RESULTS: VEGF directly increased the productions of TNF-alpha and IL-6 from peripheral blood mononuclear cells (PBMC) from healthy controls. Treatment of PBMC with anti-VEGF receptor (anti-Flt-1) mAb blocked the VEGF-induced productions of TNF-alpha and IL-6, suggesting that VEGF activates the PBMC via a receptor (Flt-1) coupling event. Synovial fluid mononuclear cells (SFMC) of RA patients showed a greater response to VEGF stimulation than the PBMC of healthy controls. The major cell types responding to VEGF were monocytes and synoviocytes. In addition, dexamethasone completely abrogated VEGF- stimulated productions of TNF-alpha and IL-6 from adherent cells, isolated from SFMC. CONCLUSION: Our data suggest that VEGF may directly activate RA monocytes and synoviocytes to produce TNF-alpha and IL-6.