Haruki Watanabe

Risk factors for the development of glucocorticoid-induced diabetes mellitus

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. 89.0mg/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/1.73m(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.

Correction: Downregulation of miR-200a-3p, Targeting CtBP2 Complex, Is Involved in the Hypoproduction of IL-2 in Systemic Lupus Erythematosus–Derived T Cells

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 A was 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.

The efficacy of add-on tacrolimus for minor flare in patients with systemic lupus erythematosus: a retrospective study

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 1.6 mg tacrolimus/day was administered for flare, while the mean GC dose was 13.7 mg/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 (9.7 mg/day vs. 7.1 mg/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.

Prognostic factors of methotrexate-associated lymphoproliferative disorders associated with rheumatoid arthritis and plausible application of biological agents

Abstract 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. Chemotherapy-free 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.

Role of Lgals9 Deficiency in Attenuating Nephritis and Arthritis in BALB/c Mice in a Pristane-Induced Lupus Model

In systemic lupus erythematosus (SLE), an autoimmune disease associated with multiple organ involvement, the development of lupus nephritis determines prognosis, and arthritis impairs quality of life. Galectin 9 (Gal‐9, Lgals9) is a β‐galactoside–binding lectin that has been used for clinical application in autoimmune diseases, since recombinant Gal‐9, as a ligand for T cell immunoglobulin and mucin domain–containing protein 3 (TIM‐3), induces apoptosis of activated CD4+TIM‐3+ Th1 cells. This study was undertaken to investigate whether deficiency of Lgals9 has beneficial or deleterious effects on lupus in a murine model.

A retrospective observational study of glucocorticoid-induced diabetes mellitus with IgA nephropathy treated with tonsillectomy plus methylprednisolone pulse therapy

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, 1.2–16.6, 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.

The Successful Treatment of Refractory Polyarteritis Nodosa Using Infliximab

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.

Bilateral Abducens Nerve Palsy due to Idiopathic Intracranial Hypertension as an Initial Manifestation of Systemic Lupus Erythematosus

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.

Hemoptysis Originating from the Bronchial Artery in Takayasu Arteritis with Ulcerative Colitis

Takayasu arteritis (TAK) is a large-vessel vasculitis affecting the aorta and its main branches. Hemoptysis can be experienced as the respiratory manifestation, but origination from a bronchial artery is rare. Ulcerative colitis (UC) shares genetic similarities with TAK; HLA-B52*01 is associated with TAK and UC. We herein report a patient who presented with hemoptysis from the right bronchial artery and was diagnosed with TAK during the follow-up of UC. Transcatheter embolization was performed, and prednisolone and tocilizumab induced remission. Complication of TAK should be considered in the clinical course of HLA-B52-positive UC patients, and tocilizumab may be a treatment option.

Cardiovocal syndrome (Ortner syndrome) associated with secondary pulmonary arterial hypertension in a patient with mixed connective tissue disease

Abstract Cardiovocal syndrome (Ortner syndrome) is characterised by a vocal hoarseness due to a left recurrent laryngeal nerve (LRLN) paralysis caused by a mechanical compression of the nerve by enlarged cardiovascular structures in various cardiovascular diseases. Here, we describe a rare laryngeal complication associated with secondary pulmonary arterial hypertension (PAH) in a patient with mixed connective tissue disease (MCTD). A 23-year-old woman who presented with hoarseness was diagnosed left vocal cord palsy by laryngofiberscopy. Further examination revealed that a secondary PAH associated with a MCTD was most likely to the cause of LRLN paralysis. Although the pulmonary artery pressure itself was rapidly normalised after the initiation of treatment with immunosuppressants and vasodilators, it took over a year for the dilation of pulmonary artery trunk as well as vocal cord palsy to improve. Laryngeal involvement is a rare complication of autoimmune diseases such as systemic lupus erythematosus (SLE) and MCTD. The identification of the cause behind the genesis of a laryngeal complication and the immediate initiation of an intensive treatment together is important to improve vocal cord palsy associated with systemic autoimmune disorders.