Language：English   Publisher：AMER ASSOC IMMUNOLOGISTS  

Systemic lupus erythematosus (SLE) damages multiple organs by producing various autoantibodies. In this study, we report that decreased microRNA (miR)-200a-3p causes IL-2 hypoproduction through zinc finger E-box binding homeobox (ZEB) 1 and C-terminal binding protein 2 (CtBP2) in a lupus-prone mouse. First, we performed RNA sequencing to identify candidate microRNAs and mRNAs involved in the pathogenesis of SLE. We found that miR-200a-3p was significantly downregulated, whereas its putative targets, ZEB2 and CtBP2, were upregulated in CD4(+) T cells from MRL/lpr-Tnfrsf6 (lpr) mice compared with C57BL/6J mice. ZEB1 and ZEB2 comprise the ZEB family and suppress various genes, including IL-2 by recruiting CtBP2. IL-2 plays a critical role in immune tolerance, and insufficient IL-2 production upon stimulation has been recognized in SLE pathogenesis. Therefore, we hypothesized that decreased miR-200a-3p causes IL-2 deficit through the ZEB1-CtBP2 and/or ZEB2-CtBP2 complex in SLE CD4(+) T cells. Overexpression of miR-200a-3p induced IL-2 production by downregulating ZEB1, ZEB2, and CtBP2 in EL4 cell lines. We further revealed that miR-200a-3p promotes IL-2 expression by reducing the binding of suppressive ZEB1-CtBP2 and ZEB2-CtBP2 complexes on negative regulatory element A in the IL-2 promoter in EL4 cells. Interestingly, the ZEB1-CtBP2 complex on negative regulatory element Awas significantly upregulated after PMA/ionomycin stimulation in lupus CD4(+) T cells. Our studies have revealed a new epigenetic pathway in the control of IL-2 production in SLE whereby low levels of miR-200a-3p accumulate the binding of the ZEB1-CtBP2 complex to the IL-2 promoter and suppress IL-2 production.

DOI： 10.4049/jimmunol.1601705

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Language：English   Publisher：AMER ASSOC IMMUNOLOGISTS  

Systemic lupus erythematosus (SLE) damages multiple organs by producing various autoantibodies. In this study, we report that decreased microRNA (miR)-200a-3p causes IL-2 hypoproduction through zinc finger E-box binding homeobox (ZEB) 1 and C-terminal binding protein 2 (CtBP2) in a lupus-prone mouse. First, we performed RNA sequencing to identify candidate microRNAs and mRNAs involved in the pathogenesis of SLE. We found that miR-200a-3p was significantly downregulated, whereas its putative targets, ZEB2 and CtBP2, were upregulated in CD4(+) T cells from MRL/lpr-Tnfrsf6 (lpr) mice compared with C57BL/6J mice. ZEB1 and ZEB2 comprise the ZEB family and suppress various genes, including IL-2 by recruiting CtBP2. IL-2 plays a critical role in immune tolerance, and insufficient IL-2 production upon stimulation has been recognized in SLE pathogenesis. Therefore, we hypothesized that decreased miR-200a-3p causes IL-2 deficit through the ZEB1-CtBP2 and/or ZEB2-CtBP2 complex in SLE CD4(+) T cells. Overexpression of miR-200a-3p induced IL-2 production by downregulating ZEB1, ZEB2, and CtBP2 in EL4 cell lines. We further revealed that miR-200a-3p promotes IL-2 expression by reducing the binding of suppressive ZEB1-CtBP2 and ZEB2-CtBP2 complexes on negative regulatory element A in the IL-2 promoter in EL4 cells. Interestingly, the ZEB1-CtBP2 complex on negative regulatory element Awas significantly upregulated after PMA/ionomycin stimulation in lupus CD4(+) T cells. Our studies have revealed a new epigenetic pathway in the control of IL-2 production in SLE whereby low levels of miR-200a-3p accumulate the binding of the ZEB1-CtBP2 complex to the IL-2 promoter and suppress IL-2 production.

DOI： 10.4049/jimmunol.1601705

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Language：English   Publisher：PUBLIC LIBRARY SCIENCE  

Aims
To evaluate the incidence of GC-DM among patients with immunoglobulin A nephropathy (IgAN) and to confirm the risk factors for the development of GC-DM.
Methods
The medical records of patients with IgAN newly treated with the protocol of tonsillectomy combined with steroid pulse therapy were reviewed. The primary outcome was the development of GC-DM within the hospitalization period and during one year of follow-up.
Results
During hospitalization, 19 of the 95 patients developed GC-DM (20.0%), and the patients with GC-DM were significantly older and had a higher rate of family history of diabetes and higher HbA1c levels. The prevalence of hypertension was higher and the eGFR was numerically lower in patients with GC-DM than in those without. Older age (>= 45 years) and a family history of diabetes emerged as independent risk factors for the development of GC-DM (odds ratio [OR], 6.3 and 95% confidence interval [CI], 1.6-27.6; OR, 4.4 and 95% CI, 1.216.6, respectively). No patients were newly diagnosed with GC-DM during 1-year observation period at out-patient clinic.
Conclusions
Among the patients with IgAN, 20% developed GC-DM during the hospitalization period, confirming the family history of diabetes is clinically necessary before starting GC therapy.

DOI： 10.1371/journal.pone.0178018

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Language：English   Publisher：JAPAN SOC INTERNAL MEDICINE  

We herein report a patient with breast cancer who developed dermatomyositis (DM) immediately after mastectomy. She had a history of severe drug eruption during neoadjuvant chemotherapy six months previously. Within a month after the operation, myalgia and rash, including Gottron's papules, developed, and skeletal-muscle enzymes elevated, so she was diagnosed with probable DM according to the Bohan and Peter criteria. In many neoplastic DM cases, the course of the disease parallels the course of the malignancy. Possible mechanisms were suggested to explain the development of DM in the present case and offer new insight into autoimmune diseases.

DOI： 10.2169/internalmedicine.9194-17

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Language：English   Publisher：JAPAN SOC INTERNAL MEDICINE  

Objective To assess the safety of azathioprine (AZA) in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV).
Methods We retrospectively enrolled 67 consecutive AAV patients who had initiated AZA treatment from January 2006 to August 2014 at Okayama University Hospital. We evaluated the development of severe adverse events (AEs), AZA discontinuation due to total AEs (severe AEs included) within 1 year, and AZA-associated risk factors.
Results The patients' median age was 70 years old. Forty-nine women and 18 men participated at the initiation of the study. Fifty-eight (87%) patients experienced AEs, and 36 experienced severe AEs (21 hepatic and 11 cytopenic severe AEs). Thirty-one (46%) patients discontinued treatment because of AEs. Abnormal hepatic laboratory test results at the treatment initiation were more frequent in patients with hepatic severe AEs and were associated with treatment discontinuation. The leukocyte and neutrophil counts at the treatment initiation were lower in the patients who discontinued treatment because of cytopenic AEs than in those who continued treatment. Only two patients experienced flare-ups during treatment.
Conclusion The AE-associated AZA discontinuation rate in Japanese AAV patients was relatively high. AZA use warrants caution in patients with abnormal hepatic laboratory test results or low leukocyte or neutrophil counts.

DOI： 10.2169/internalmedicine.56.8287

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Language：English   Publisher：TAYLOR & FRANCIS LTD  

Objectives: To determine prognostic factors of methotrexate-associated lymphoproliferative disorder (MTX-LPD) and evaluate the efficacy and safety of biological therapy in rheumatoid arthritis (RA) complicated with MTX-LPD.
Methods: Thirty RA patients who developed MTX-LPD were investigated in this study. We compared the clinical and laboratory parameters of patients who achieved regression of LPD by MTX withdrawal with those who required chemotherapy and evaluated the clinical course of RA after LPD development.
Results: Twenty-three patients (76.7%) achieved regression of LPD by MTX withdrawal. Chemotherapyfree patients had a tendency of shorter RA duration (13.1 vs. 22.0 years, p = 0.108) and higher doses of MTX at LPD diagnosis (8.0 vs. 5.3 mg/w, p = 0.067) than patients who required chemotherapy. A significantly higher positive rate of peripheral blood Epstein-Barr virus (EBV)-DNA was observed in the chemotherapy-free group (9/9 vs. 0/3, p = 0.0002). Of 15 patients that received biological agents after LPD development, 14 patients (93.3%) demonstrated an improved disease activity of RA and persistent remission of LPD, whereas only one patient experienced relapse of LPD during tocilizumab therapy.
Conclusions: Peripheral blood EBV-DNA positivity is a potential prognostic marker of better outcome in MTX-LPD. Biological agents could be an option for the treatment of RA patients with MTX-LPD.

DOI： 10.1080/14397595.2016.1259714

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Language：English   Publisher：JAPAN SOC INTERNAL MEDICINE  

We herein describe two cases of refractory antineutrophil cytoplasmic antibody-associated vasculitis (AAV) complicated with diabetes insipidus (DI) possibly related to hypertrophic pachymeningitis (HP). One patient had microscopic polyangiitis and HP, which were refractory to cyclophosphamide, azathioprine, rituximab, mycophenolate mofetil (MMF), and mizoribine. Remission was finally achieved with the use of etanercept, but DI occurred 5 years later. The other patient had granulomatosis with polyangiitis, which that was refractory to cyclophosphamide, methotrexate, MMF, and rituximab. DI subsequently developed, but was successfully treated with etanercept. Dura mater hypertrophy was macroscopically observed in the latter case.

DOI： 10.2169/internalmedicine.8683-16

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Language：English   Publisher：JAPAN SOC INTERNAL MEDICINE  

We herein describe two cases of refractory antineutrophil cytoplasmic antibody-associated vasculitis (AAV) complicated with diabetes insipidus (DI) possibly related to hypertrophic pachymeningitis (HP). One patient had microscopic polyangiitis and HP, which were refractory to cyclophosphamide, azathioprine, rituximab, mycophenolate mofetil (MMF), and mizoribine. Remission was finally achieved with the use of etanercept, but DI occurred 5 years later. The other patient had granulomatosis with polyangiitis, which that was refractory to cyclophosphamide, methotrexate, MMF, and rituximab. DI subsequently developed, but was successfully treated with etanercept. Dura mater hypertrophy was macroscopically observed in the latter case.

DOI： 10.2169/internalmedicine.8683-16

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Language：English   Publisher：JAPAN SOC INTERNAL MEDICINE  

We herein report a patient with breast cancer who developed dermatomyositis (DM) immediately after mastectomy. She had a history of severe drug eruption during neoadjuvant chemotherapy six months previously. Within a month after the operation, myalgia and rash, including Gottron's papules, developed, and skeletal-muscle enzymes elevated, so she was diagnosed with probable DM according to the Bohan and Peter criteria. In many neoplastic DM cases, the course of the disease parallels the course of the malignancy. Possible mechanisms were suggested to explain the development of DM in the present case and offer new insight into autoimmune diseases.

DOI： 10.2169/internalmedicine.9194-17

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DOI： 10.1080/14397595.2017.1317377

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Language：English   Publisher：JAPAN SOC INTERNAL MEDICINE  

Objective To assess the safety of azathioprine (AZA) in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV).
Methods We retrospectively enrolled 67 consecutive AAV patients who had initiated AZA treatment from January 2006 to August 2014 at Okayama University Hospital. We evaluated the development of severe adverse events (AEs), AZA discontinuation due to total AEs (severe AEs included) within 1 year, and AZA-associated risk factors.
Results The patients' median age was 70 years old. Forty-nine women and 18 men participated at the initiation of the study. Fifty-eight (87%) patients experienced AEs, and 36 experienced severe AEs (21 hepatic and 11 cytopenic severe AEs). Thirty-one (46%) patients discontinued treatment because of AEs. Abnormal hepatic laboratory test results at the treatment initiation were more frequent in patients with hepatic severe AEs and were associated with treatment discontinuation. The leukocyte and neutrophil counts at the treatment initiation were lower in the patients who discontinued treatment because of cytopenic AEs than in those who continued treatment. Only two patients experienced flare-ups during treatment.
Conclusion The AE-associated AZA discontinuation rate in Japanese AAV patients was relatively high. AZA use warrants caution in patients with abnormal hepatic laboratory test results or low leukocyte or neutrophil counts.

DOI： 10.2169/internalmedicine.56.8287

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Language：English   Publisher：JAPAN SOC INTERNAL MEDICINE  

Polyarteritis nodosa (PAN), characterized by arteritis of medium-sized blood vessels, is usually treated with a combination of glucocorticoids and immunosuppressants; however, some cases are refractory to these treatments. We herein report the case of a man with PAN that was refractory to various immunosuppressive treatments, including cyclophosphamide, methotrexate, and rituximab. After infliximab (IFX) treatment was initiated, his symptoms improved dramatically and remission was maintained. IFX is considered to be an effective alternative treatment for PAN which proves to be refractory to several immunosuppressive treatments.

DOI： 10.2169/internalmedicine.56.8235

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Language：English   Publisher：JAPAN SOC INTERNAL MEDICINE  

Polyarteritis nodosa (PAN), characterized by arteritis of medium-sized blood vessels, is usually treated with a combination of glucocorticoids and immunosuppressants; however, some cases are refractory to these treatments. We herein report the case of a man with PAN that was refractory to various immunosuppressive treatments, including cyclophosphamide, methotrexate, and rituximab. After infliximab (IFX) treatment was initiated, his symptoms improved dramatically and remission was maintained. IFX is considered to be an effective alternative treatment for PAN which proves to be refractory to several immunosuppressive treatments.

DOI： 10.2169/internalmedicine.56.8235

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Language：English   Publisher：SAGE PUBLICATIONS LTD  

Objective We have assessed the effectiveness of tacrolimus for minor flares in systemic lupus erythematosus (SLE) patients.
Methods The medical records of 313 patients were retrospectively reviewed over a period of seven years, from 2006 to 2013. We enrolled patients with minor flare treated with add-on tacrolimus, without glucocorticoid (GC) intensification (tacrolimus group). Minor flare was defined as a 1-point increase in a total score between 3 and 11 in the SLE Disease Activity Index (SLEDAI). We enrolled as controls patients who were administered increased doses of GC for minor flare (GC group). All patients were followed for one year. The primary outcome measure was the proportion of responders.
Results There were 14 eligible patients in the tacrolimus group and 20 eligible patients in the GC group. The mean SLEDAI at flare tended to be higher in the tacrolimus group than in the GC group (7.5 vs. 6.2, p=0.085). A mean dose of 1.6mg tacrolimus/day was administered for flare, while the mean GC dose was 13.7mg/day in the GC group. The proportion of responders was 86% (12/14) in the tacrolimus group and 75% (15/20) in the GC group (p=0.67). The mean dose of GC at 12 months was higher in the GC group than in the tacrolimus group (9.7mg/day vs. 7.1mg/day, p<0.05). Only one patient discontinued tacrolimus because of fatigue after three months.
Conclusion Adding tacrolimus without increasing the GC dose may provide an effective treatment option for minor flares in patients with SLE.

DOI： 10.1177/0961203315600538

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Language：English   Publisher：SAGE PUBLICATIONS LTD  

Objective We have assessed the effectiveness of tacrolimus for minor flares in systemic lupus erythematosus (SLE) patients.
Methods The medical records of 313 patients were retrospectively reviewed over a period of seven years, from 2006 to 2013. We enrolled patients with minor flare treated with add-on tacrolimus, without glucocorticoid (GC) intensification (tacrolimus group). Minor flare was defined as a 1-point increase in a total score between 3 and 11 in the SLE Disease Activity Index (SLEDAI). We enrolled as controls patients who were administered increased doses of GC for minor flare (GC group). All patients were followed for one year. The primary outcome measure was the proportion of responders.
Results There were 14 eligible patients in the tacrolimus group and 20 eligible patients in the GC group. The mean SLEDAI at flare tended to be higher in the tacrolimus group than in the GC group (7.5 vs. 6.2, p=0.085). A mean dose of 1.6mg tacrolimus/day was administered for flare, while the mean GC dose was 13.7mg/day in the GC group. The proportion of responders was 86% (12/14) in the tacrolimus group and 75% (15/20) in the GC group (p=0.67). The mean dose of GC at 12 months was higher in the GC group than in the tacrolimus group (9.7mg/day vs. 7.1mg/day, p<0.05). Only one patient discontinued tacrolimus because of fatigue after three months.
Conclusion Adding tacrolimus without increasing the GC dose may provide an effective treatment option for minor flares in patients with SLE.

DOI： 10.1177/0961203315600538

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DOI： 10.1080/14397595.2016.1259714

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Language：English   Publisher：JAPAN SOC INTERNAL MEDICINE  

Idiopathic intracranial hypertension (IIH) is a syndrome of increased intracranial pressure and presents as an intractable headache, vomiting, and ophthalmologic manifestations. We herein report the case of a young girl who presented with bilateral abducens nerve palsy due to IIH as the onset of systemic lupus erythematosus (SLE). The patient was successfully treated with corticosteroid therapy. Our case lacked the typical symptoms of IIH, such as headache or nausea; therefore, it is necessary to carefully determine the cause of bilateral abducens nerve palsies. The development of IIH in SLE patients is a rare occurrence, but this manifestation should not be overlooked.

DOI： 10.2169/internalmedicine.55.5990

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Language：English   Publisher：ELSEVIER IRELAND LTD  

Aims: To evaluate the incidence of glucocorticoid-induced diabetes mellitus (GC-DM) by repeated measurements of the postprandial glucose and detect predictors for the development of GC-DM.
Methods: Inpatients with rheumatic or renal disease who received glucocorticoid therapy were enrolled in this study. We compared the clinical and laboratory parameters of the GC-DM group with the non-GC-DM group and performed a multivariate analysis to identify risk factors.
Results: During a four-week period, 84 of the 128 patients (65.6%) developed GC-DM. All patients were diagnosed based on the detection of postprandial hyperglycemia. The GC-DM group had an older age (65.2 vs. 50.4 years, p < 0.0001), higher levels of fasting plasma glucose (93.3 vs. 89.0 mg/dl, p = 0.027) and HbA1c (5.78 vs. 5.50%, 39.7 vs. 36.6 mmol/mol, p = 0.001) and lower eGFR values (54.0 vs. 77.1 ml/min/1.73 m(2), p = 0.0003) than the non-GC-DM group. According to the multivariate analysis, an older age (more than or equal to 65 years), higher HbA1c level (more than or equal to 6.0%) and lower eGFR (<40 ml/min/1.73 m(2)) were identified as independent risk factors for GC-DM (OR 2.95, 95% CI 1.15-7.92, OR: 3.05, 95% CI 1.11-9.21, OR: 3.42, 95% CI: 1.22-10.8, respectively). The risk ratio for the development of GC-DM in the patients with at least one of these three risk factors was 2.28. The dose of glucocorticoids was not statistically related to the development of GC-DM.
Conclusions: Patients with an older age, higher HbA1c level and lower eGFR require close monitoring for the development of GC-DM, regardless of the dose of glucocorticoids being administered. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.diabres.2015.02.010

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