Role of the CCL20/CCR6 axis in tubular epithelial cell injury: Kidney-specific translational insights from acute kidney injury to chronic kidney disease.

This study investigated the role of the axis involving chemokine receptor 6 (CCR6) and its ligand chemokine (C-C motif) ligand 20 (CCL20) in acute kidney disease (AKD) using an ischemia-reperfusion injury (IRI) model. The model was established by clamping the unilateral renal artery pedicle of C57BL/6 mice for 30 min, followed by evaluation of CCL20/CCR6 expression at 4 weeks post-IRI. In vitro studies were conducted to examine the effects of hypoxia and H2 O2 -induced oxidative stress on CCL20/CCR6 expression in kidney tissues of patients with AKD and chronic kidney disease (CKD). Tubular epithelial cell apoptosis was more severe in C57BL/6 mice than in CCL20 antibody-treated mice, and CCR6, NGAL mRNA, and IL-8 levels were higher under hypoxic conditions. CCL20 blockade ameliorated apoptotic damage in a dose-dependent manner under hypoxia and reactive oxygen species injury. CCR6 expression in IRI mice indicated that the disease severity was similar to that in patients with the AKD phenotype. Morphometry of CCL20/CCR6 expression revealed a higher likelihood of CCR6+ cell presence in CKD stage 3 patients than in stage 1-2 patients. Kidney tissues of patients with CKD frequently contained CCL20+ cells, which were positively correlated with interstitial inflammation. CCL20/CCR6 levels were increased in fibrotic kidneys at 4 and 8 weeks after 5/6 nephrectomy. These findings suggest that modulating the CCL20/CCR6 pathway is a potential therapeutic strategy for managing the progression of AKD to CKD.

Association between knee osteoarthritis and mortality: a serial propensity score-matched cohort study.

BACKGROUND/AIMS: The association between symptomatic knee osteoarthritis (OA) and higher cardiovascular disease (CVD) mortality is established; however, findings from studies that utilized regression analysis were limited, attributed to the strong association between OA and metabolic risk factors. This study aimed to evaluate the association between knee OA and mortality through propensity score matching. METHODS: This was a cohort study including Korean National Health and Nutrition Examination Survey (2010-2013) participants aged ≥ 50 years. By linking the survey data to cause of death data (through 2019) from Statistics Korea, mortality and cause-specific mortality data were obtained. Radiographic knee OA (ROA) was defined as bilateral Kellgren-Lawrence grade ≥ 2. Propensity score matching (1:1) was conducted between asymptomatic ROA, knee pain, and symptomatic ROA groups and normal groups, balancing the confounding factors. Time to death was analyzed using Cox proportional hazard modeling. RESULTS: A higher CVD mortality was observed in the symptomatic ROA group, but not in others; the risk estimates were asymptomatic ROA (hazard ratio [HR] 1.12; 95% confidence interval [CI] 0.77-1.65), knee pain (HR 0.61; 95% CI 0.27-1.38), and symptomatic ROA (HR 1.39; 95% CI 0.89-2.17). No association was found between the all-cause/cancer mortality and other groups. CONCLUSION: When propensity score matching controls metabolic risk factor imbalances, the association between symptomatic knee OA and higher CVD mortality was weaker compared to results of prior studies that used regression adjustment. The results may be more precise estimates of the total risk of knee OA for mortality in Koreans.

Risk of progression of idiopathic pulmonary fibrosis to connective tissue disease: a long-term observational study in 527 patients.

OBJECTIVE: Connective tissue disease (CTD) might occur during the course of idiopathic pulmonary fibrosis (IPF). Clinical factors associated with CTD development in IPF patients have still not been identified. We investigated which antibodies have a significant association with the development of CTD during the clinical course of IPF. METHODS: We retrospectively reviewed the records of 527 patients with a first diagnosis of IPF between January 2007 and March 2014 and investigated the time to CTD development after IPF diagnosis in these patients. RESULTS: CTD developed in 15 patients at a median of 2.1 years (range 1.2-4.8) after IPF diagnosis. All patients had anti-neutrophil cytoplasmic antibodies (ANCA) or autoantibodies that met the serology criteria for interstitial pneumonia with autoimmune features (IPAF). Survival duration for IPF patients with progression to CTD was 5.3 (3.8, 6.7) years, which was significantly longer than for IPF patients without progression to CTD [2.9 (1.7, 4.8), p = 0.001]. Independent risk factors for CTD development in IPF patients included female gender [adjusted hazard ratio (HR) 5.319, p = 0.0082], titer of rheumatoid factor (RF; adjusted HR, 1.006; p = 0.022), titer of anti-citrullinated protein antibody (ACPA; adjusted HR, 1.009; p = 0.0011), and titer of myeloperoxidase (MPO)-ANCA (adjusted HR, 1.02; p < 0.0001). CONCLUSION: Progression to CTD is uncommon in IPF patients. However, a significant number of IPF patients with high titers of RF, ACPA, or MPO-ANCA progressed to CTD. RF, ACPA, and MPO-ANCA might be significantly associated with CTD development in IPF patients. Key Points • A significant number of IPF patients with high titers of RF, ACPA, or MPO-ANCA progressed to CTD. • IPF/UIP with high titers of RF, ACPA, or MPO-ANCA might be the initial clinical manifestation of CTD. • RF, ACPA, and MPO-ANCA may be significantly associated with the development of pulmonary fibrosis in patients with CTD.

Clinically amyopathic dermatomyositis presenting with isolated facial edema complicated by acute respiratory failure: a case report.

BACKGROUND: In clinically amyopathic dermatomyositis, the hallmark cutaneous manifestations are the key to diagnosis. We report a case of clinically amyopathic dermatomyositis which presented with facial edema as the sole cutaneous manifestation and was later complicated by acute respiratory failure leading to death. CASE PRESENTATION: A 58-year-old woman presented with edema of the face that had developed approximately one year ago. There was no weakness in the extremities, and the serum creatine kinase level was within normal range. On MRI, there was diffuse edematous change in the bilateral masticator and extra-ocular muscles, accompanied by subcutaneous fat infiltration in the face. A shared decision was made to defer muscle biopsy in the facial muscles. The facial swelling almost resolved with medium-dose glucocorticoid therapy but relapsed in days at glucocorticoid doses lower than 15 mg/day. Combination therapy with either azathioprine, mycophenolate, or methotrexate was not successful in maintaining clinical remission, and the swelling became more severe after relapses. A US-guided core-needle biopsy was subsequently performed in the right masseter muscle. On pathologic examination, there was a patchy CD4 + T cell-dominant lymphoplasmacytic infiltration in the stroma, necrosis of the myofibrils and prominent perifascicular atrophy. Based on those findings, a diagnosis of clinically amyopathic dermatomyositis was made. Therapy with gamma-globulin was not effective in maintaining remission. In the sixth week after starting rituximab, she presented to emergency room with altered mental state from acute respiratory failure. Despite treatment with antibiotics, glucocorticoid pulse, cyclosporin, and polymyxin B-immobilized fiber column direct hemoperfusion, she died three weeks later from persistent hypoxemic respiratory failure. CONCLUSIONS: This case showed the full spectrum and severity of internal organ involvement of dermatomyositis, although the patient presented exclusively with subcutaneous edema limited to the head. The prognosis may be more closely associated with a specific auto-antibody profile than the benign-looking initial clinical manifestation. Close follow-up of lung involvement with prophylactic treatment for Pneumocystis pneumonia and prompt implementation of emerging therapeutic regimens may improve the outcome.

Efficacy and tolerability of febuxostat in gout patients on dialysis.

BACKGROUND: There are no sufficient data available on the use of febuxostat in patients undergoing dialysis. AIM: To investigate the efficacy and tolerability of febuxostat in gout patients on dialysis. METHODS: We retrospectively reviewed clinical and laboratory data available from a referral centre from January 2012 to December 2018. We included gout patients who initiated febuxostat during dialysis. Data regarding serum uric acid levels before and after the febuxostat treatment and clinical information such as gout attack after febuxostat initiation, as well as adverse events involving febuxostat treatment, were obtained from medical records. RESULTS: Among 62 patients who were treated with febuxostat for over 3 months, 45 were undergoing haemodialysis (HD) and 17 were undergoing peritoneal dialysis (PD). The mean serum uric acid level was significantly reduced 3 months after treatment (3.71 ± 1.32 mg/dL) compared with that at the pretreatment level (9.36 ± 2.06 mg/dL) (P < 0.001). The serum uric acid level was observed to be significantly reduced at 3 months in both HD and PD patients and subsequently remained at a significantly reduced level for 12 months. Of the 62 patients, only two stopped febuxostat due to its adverse effects. Initial dose of 80 mg/day was associated with higher adverse events compared to dose of 20-40 mg/day (odds ratio 8.25, 95% confidence interval 1.90-35.97, P = 0.006). CONCLUSIONS: Febuxostat is efficacious and well tolerated in gout patients on dialysis. Febuxostat taken at dose of 20-40 mg/day might be appropriate initial dose in patients undergoing dialysis.

Effect of TNF inhibitors on bone mineral density in rheumatoid arthritis patients receiving bisphosphonate: a retrospective cohort study.

We aimed to determine whether tumor necrosis factor inhibitors (TNFi) have beneficial effects on bone mineral density (BMD) in rheumatoid arthritis (RA) patients with osteoporosis receiving bisphosphonate. A total of 199 RA patients, who were newly diagnosed with osteoporosis and receiving bisphosphonate between January 2005 and March 2017, were reviewed. Changes in BMD after 1 year were compared between patients treated with and without TNFi. The inverse probability of treatment weighting (IPTW) method using the propensity score was performed to minimize confounding factors, and logistic regression analysis was applied to identify any factors associated with significant BMD improvement (≥ 3%) at the lumbar spine and femur neck. Among patients receiving bisphosphonate, 29 were exposed to TNFi, and 170 patients were not exposed. The percentage change in BMD and the proportion of significant improvements at the lumbar spine and femur neck were similar between patients treated with and without TNFi, before and after IPTW adjustment. In addition, the disease activity score 28 (DAS28) with three variables [adjusted odds ratio (OR) 0.741, 95% confidence interval (CI) 0.592-0.927, p = 0.009] and cumulative steroid dose (adjusted OR 0.639, 95% CI 0.480-0.851, p = 0.002) were inversely associated with an improvement in BMD. Conversely, TNFi use was not associated with any improvement in BMD after adjustment by IPTW using the propensity score. TNFi did not influence BMD improvement in RA patients with osteoporosis receiving bisphosphonate, suggesting that TNFi cannot be considered as a preferred therapeutic option for increasing BMD.

Effect of tumor necrosis factor inhibition on spinal inflammation and spinal ankylosis in SKG mice.

To prevent spinal progression in ankylosing spondylitis, initiating TNF-inhibitor treatment as early as possible is suggested. However, the outcomes are inconsistent in previous clinical studies. Here, we investigated the effect of TNF inhibition alone on spinal progression when used during arthritis development in a murine model. We injected 8-week-old SKG mice with curdlan (curdlan group). We injected adalimumab at 3 and 9 weeks after the first curdlan injection (ADA group). The clinical scores of peripheral arthritis decreased in the ADA group at 3 weeks after first adalimumab injection. Using positron emission tomography-magnetic resonance imaging and histologic examination, spinal inflammation was observed in the curdlan group, and was significantly deceased in the ADA group. However, spinal osteoblast activities by imaging using OsteoSense 680 EX and bone metabolism-related cytokines such as receptor activator of nuclear factor-kappa B ligand, osteoprotegerin, Dickkopf-1, and sclerostin levels except IL-17A level were not different between the two groups. We conclude that treating TNF inhibitor alone reduced peripheral arthritis score and spinal inflammation in curdlan-injected SKG mice but did not decrease the spinal osteoblast activity, suggesting little effect on spinal ankylosis.

Clinical features and prognoses of acute transverse myelitis in patients with systemic lupus erythematosus.

BACKGROUND/AIMS: Acute transverse myelitis (ATM) is a severe complication of systemic lupus erythematosus (SLE). This study evaluated the clinical factors related to outcome in patients with SLE-associated ATM. METHODS: The medical records of patients diagnosed with SLE-associated ATM between January 1995 and January 2015 were reviewed. The patients were divided into two groups based on improvement of neurological deficits after treatment: favorable response group and unfavorable response group. During follow-up, the recurrence of ATM was also analyzed. RESULTS: ATM was identified in 16 patients with SLE. All of the patients were treated with high doses of methylprednisolone (≥ 1 mg/kg daily). Although 12 patients (75%) recovered (favorable response group), four (25%) had persistent neurologic deficits (unfavorable response group) after the treatment. Compared to the favorable response group, significantly higher Systemic Lupus Erythematosus Disease Activity Index-2000, lower complement levels and initial severe neurologic deficits were found in the unfavorable response group. Among the 12 favorable response patients, five (41.7%) experienced recurrence of ATM during the followup. Patients (n = 5) who experienced relapse had a shorter duration of high-dose corticosteroid treatment (13.2 days vs. 32.9 days, p = 0.01) compared to patients who did not relapse. The mean duration of tapering-off the corticosteroid until 10 mg per day was significantly longer in non-relapse group (151.3 ± 60.8 days) than in relapse group (63.6 ± 39.4 days, p = 0.013). CONCLUSION: Higher disease activity in SLE and initial severe neurologic deficits might be associated with the poor outcome of ATM. Corticosteroid slowly tapering-off therapy might be helpful in preventing the recurrence of ATM.

The risk of herpes zoster in patients with ankylosing spondylitis: Analysis of the Korean National Health Insurance Service - Sample cohort database.

OBJECTIVES: The aims of our study were to determine whether the use of conventional disease-modifying antirheumatic drugs (cDMARDs) or tumor necrosis factor α (TNFα) inhibitors increase the risk of herpes zoster (HZ) in patients with ankylosing spondylitis (AS). METHODS: We searched the South Korean National Health Insurance Service - National Sample Cohort Database for relevant patient records between 2002 and 2013. We evaluated the incidence of HZ by categorizing patients into in three treatment groups: disease-modifying antirheumatic drug (DMARD) nonusers, cDMARD users and TNFα inhibitor users. RESULTS: Incidence rates of HZ was 11.0 per 1000 person-years in patients with AS. The adjusted hazard ratio of HZ was higher in cDMARD and TNFα inhibitor users than in DMARD nonusers. In subgroup analyses, current treatment with a TNFα inhibitor increased the risk of HZ significantly both in female patients and in patients aged 50 years or older, but not in patients taking steroids, compared to DMARD nonusers. CONCLUSIONS: Treatment with either TNFα inhibitors or cDMARDs is associated with a higher risk of HZ, especially in female patients and older patients, and these two patient groups could therefore benefit from HZ vaccination.

Ileocolonoscopic findings in patients with ankylosing spondylitis: a single center retrospective study.

BACKGROUND/AIMS: In some Western countries, up to 50% of patients with ankylosing spondylitis (AS) have subclinical gut inflammation. This study was conducted to evaluate the prevalence and severity of gut inflammation and to determine clinical factors associated with colonic inflammation in Korean AS patients who performed ileocolonoscopy without evidence of established inf lammatory bowel diseases before. METHODS: One hundred and eight AS patients who underwent ileocolonoscopy were included in this study. Patients were divided into two groups based on gross ileocolonoscopic findings; patients with inflammatory lesions, and patients without inflammatory lesions. RESULTS: Inf lammatory lesions in ileocolonoscopic findings were found in 40 patients. The Ankylosing Spondylitis Disease Activity Score C-reactive protein was higher in the group with inflammatory lesions and gut lesions were found often in the terminal ileum. The risk of inflammatory lesions was higher for AS patients whose symptoms required ileocolonoscopy than for AS patients who underwent routine ileocolonoscopy screening (odds ratio, 3.96). However, abnormal lesions were detected also in 17.6% of the patients who underwent ileocolonoscopy for routine screening and most of them were erosion and ulcer. Among patients with inflammatory lesions (n = 40), 23 showed subclinical gut inflammation associated with AS and 17 were diagnosed finally as Crohn's disease (n = 12), intestinal tuberculosis (n = 4), and ulcerative colitis (n = 1). CONCLUSIONS: Our findings suggest that ileocolonoscopy might be recommended regularly in AS patients even without gastrointestinal symptoms, especially in the patients with high AS activity.

Immunoglobulin G Levels as a Prognostic Factor for Autoimmune Hepatitis Combined With Systemic Lupus Erythematosus.

OBJECTIVE: Autoimmune hepatitis (AIH) is a chronic progressive liver disease characterized by circulating autoantibodies and hyperglobulinemia. This study was conducted to identify the features of AIH accompanied by systemic lupus erythematosus (SLE-AIH) that differ from those of primary AIH (P-AIH), and to evaluate factors that affect the outcome for SLE-AIH patients. METHODS: From May 1995 to April 2014, clinical data (including liver pathology) from 164 patients with P-AIH and 23 patients with SLE-AIH were collected from an electronic database at a tertiary referral center. AIH was diagnosed according to the diagnostic scoring system for AIH (revised in 1999). SLE patients fulfilled at least 4 of the 1997 revised American College of Rheumatology criteria. Progression was defined as occurrence of cirrhosis, hepatocellular carcinoma, liver transplantation, or death from hepatic failure. RESULTS: The age at the time of AIH diagnosis was lower and initial levels of serum IgG were higher in SLE-AIH than in P-AIH patients. Progression was more common in P-AIH, and hepatocellular carcinoma, liver transplantation, or death occurred only in P-AIH patients. Among 23 patients with SLE-AIH, 8 with cirrhosis had higher levels of serum IgG than 15 patients without cirrhosis (mean ± SD 4,077.4 ± 1,641.0 mg/dl and 2,560.7 ± 932.2 mg/dl, respectively; P = 0.017). Moreover, a serum IgG level more than 2-fold the upper normal limit was associated with a high risk of cirrhosis in SLE-AIH (odds ratio 11.00 [95% confidence interval 1.420-85.201]; P = 0.026). CONCLUSION: Initially high levels of serum IgG are a poor prognostic factor for SLE-AIH. Additionally, the long-term outcome for SLE-AIH might be better than for P-AIH.

Safety of tumor necrosis factor inhibitor therapy in patients with a prior malignancy.

AIM: There is insufficient evidence to determine whether tumor necrosis factor inhibitor (TNFi) therapy is safe in patients with a recent history of cancer. The purpose of our study was to explore the influence of TNFi therapy on cancer-related outcomes in patients who had undergone curative cancer treatment. METHODS: The medical records of 814 patients who received TNFi therapy at a single rheumatology clinic, between June 2005 and May 2014 were retrospectively reviewed. Among them, the data from patients having received anticancer treatment before starting TNFi therapy were collected and cancer-related outcomes were evaluated. RESULTS: Twenty patients of 814 had a history of malignancy before initiating TNFi therapy. Over the duration of TNFi exposure (median, 54.0 months; interquartile range [IQR], 23.25-72.0 months), there was no recurrence of the previous cancer. In eight patients with early-stage cancer, TNFi therapy was initiated < 5 years after conclusion of previous anticancer treatments. Notably, over the duration of the ongoing treatment follow-up period (median, 33.5 months; IQR, 13.0-75.75 months), cancer recurrence was also not identified. CONCLUSION: TNFi therapy in patients with a history of an early-stage localized cancer may not be contraindicated, even if TNFi is initiated < 5 years from completion of curative cancer treatment.

Clinical outcomes of hydronephrosis in patients with systemic lupus erythematosus.

AIM: Hydronephrosis is a rare complication of systemic lupus erythematosus (SLE). Bladder and/or gastrointestinal involvement in SLE are associated with development of hydronephrosis, but the management and treatment outcomes of hydronephrosis are largely unknown. Therefore, we investigated the clinical manifestations and factors associated with the treatment response in patients with SLE complicated by hydronephrosis. METHOD: A retrospective analysis was performed of all 634 SLE patients who underwent computed tomography and/or ultrasonography between January 1998 and December 2013. We reviewed the clinical characteristics and treatment outcomes of patients with SLE-associated hydronephrosis. RESULTS: Hydronephrosis was identified in 15 patients with SLE complicated by cystitis and/or enteritis. All patients were treated initially with moderate to high doses of corticosteroids. A follow-up imaging study showed that 11 (73.3%) of 15 patients experienced improvements in hydronephrosis, and urinary obstruction was resolved without urological intervention in the majority of these patients (8/11, 72.7%). The four patients who experienced no improvement in hydronephrosis were older than those who responded to treatment (median age [interquartile range]; 43.0 [37.5-53.0] years vs. 28.0 [21.0-38.5] years; P = 0.026). In addition, delayed treatment (≥ 1 month after onset of symptoms) with corticosteroids was more frequently observed in the non-responding patients than in the responding patients (P = 0.011). CONCLUSION: Our findings suggest that treatment with corticosteroids alone leads to favorable outcomes in patients with SLE-associated hydronephrosis, except when treatment is delayed, particularly in elderly patients.

Conventional Cisplatin-Based Combination Chemotherapy Is Effective in the Treatment of Metastatic Spermatocytic Seminoma with Extensive Rhabdomyosarcomatous Transformation.

A 52-year-old man was presented with a huge left testicular mass and palpable cervical lymphadenopathy with retroperitoneal lymph node enlargement on an abdominal computed tomography. A left radical orchiectomy and an ultrasound-guided neck node biopsy were performed. A pathological examination revealed spermatocytic seminoma with extensive rhabdomyosarcomatous transformation, a condition known to be highly resistant to platinum-based chemotherapy. The patient received four cycles of etoposide, ifosfamide and cisplatin (VIP) chemotherapy. A repeat computed tomography revealed a substantial regression consistent with a partial response. Retroperitoneal lymph node dissection was attempted, which revealed rhabdomyosarcoma; however, complete microscopic resection was not achieved. After surgery, the residual abdominal lymph node progressed and salvage paclitaxel, ifosfamide and cisplatin (TIP) chemotherapy was employed, which again achieved a partial response. Here, we present a first case report of a spermatocytic seminoma with extensive rhabdomyosarcomatous transformation and multiple metastatic lymphadenopathies that showed a favorable response to platinum-based systemic chemotherapy.

TNF-α confers resistance to Fas-mediated apoptosis in rheumatoid arthritis through the induction of soluble Fas.

AIMS: Rheumatoid arthritis (RA) is a chronic inflammatory arthritis that is characterized by hyperplastic synovial tissue containing activated synovial fibroblasts. Contradictory findings in the apoptosis of fibroblast-like synoviocytes (FLS) have been described elsewhere, showing that RA FLS have an enhanced susceptibility to Fas (also known as CD95)-mediated apoptosis in vitro in contrast to the observed lack of apoptosis in the RA synovium in vivo. However, the potential mechanisms responsible for this discrepancy remain under investigation. The soluble form of Fas (sFas) was found to inhibit Fas-induced apoptosis by binding to Fas ligand (FasL), thereby preventing the interaction between FasL and membrane-bound Fas. MAIN METHODS: We determined the levels of soluble FasL (sFasL) and sFas in patients with RA and the effects of proinflammatory mediators, including TNF-α, on the induction of apoptotic mediators in RA FLS. KEY FINDINGS: The levels of sFasL and sFas were significantly elevated in the synovial fluids of RA patients compared with control subjects. In addition, we found that the sFas is substantially induced in RA FLS by TNF-α, which were abundantly present in the synovial fluid of RA. SIGNIFICANCE: These findings suggest that TNF-α confers resistance to Fas-mediated apoptosis through sFas induction, which could explain the apparent resistance of RA synovial cells to apoptosis in vivo.

Polypoid arteriovenous malformation presenting with jejunojejunal intussusceptions in an adult.

Jejunal polypoid arteriovenous malformations (AVMs) and jejunojejunal intussusceptions are both rare. Here, we present the case of a 61-year-old woman who suffered intermittent episodes of abdominal pain over the course of 13 years. A computed tomography scan of her abdomen and pelvis revealed a distal jejunojejunal intussusception. A suspected low density mass was observed at the tip of the intussusception. Treatment comprised laparoscopic small bowel resection with end-to-end jejunostomy. The final diagnosis was a polypoid AVM measuring 5×3.5×3 cm. We suggest that polypoid AVM should be considered as a differential diagnosis in patients presenting with small intestinal neoplasms.