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Age-related Epstein-Barr virus (EBV)-positive B-cell lymphoproliferative disorder (LPD) occurs in elderly patients without immunodeficiency. An 81-year-old woman without any known immunodeficiency was examined for fever, rash, arthritis, thrombocytopenia, pleural and pericardial effusions, lymphadenopathy, and positive autoantibodies, which satisfied the classification criteria for systemic lupus erythematosus (SLE). However, a lymph node biopsy revealed EBV-LPD, and she was diagnosed with age-related EBV-LPD. In young individuals, EBV infection is a major differential diagnosis of SLE, but to our knowledge, this is the first reported case of age-related EBV-LPD mimicking SLE. We should therefore consider EBV-related disorders in the differential diagnosis of SLE even in elderly individuals.

Context Primary macronodular adrenal hyperplasia (PMAH) is a rare type of Cushing or subclinical Cushing syndrome and is associated with bilateral multinodular formation. ARMC5 is one of the responsible genes for PMAH. Objectives This study was performed to identify the genotype-phenotype correlation of ARMC5 in a cohort of Japanese patients. Patients and Methods Fourteen patients with clinically diagnosed PMAH and family members of selected patients were studied for ARMC5 gene alteration and clinical phenotype. The associated nonadrenal tumor tissues were also studied. Results Of fourteen patients with PMAH, 10 had pathogenic or likely pathogenic variants of ARMC5. We found two variants. Five unrelated patients had identical variants (p.R619*). In two patients, the variant was found in offspring with the asymptomatic or presymptomatic state. Six of ten patients who tested positive for the ARMC5 pathogenic or likely pathogenic variant carried nonadrenal tumors; however, no loss of heterozygosity (LOH) or second hit of the ARMC5 gene was evident. The ARMC5 variant–positive group showed a significantly higher basal cortisol level. Furthermore, age-dependent cortisol hypersecretion was seen in the ARMC5 variant–positive group. Conclusions ARMC5 pathogenic variants are common (71%) in Japanese patients with PMAH. p.R619* might be a hot spot in Japanese patients with PMAH. Asymptomatic or presymptomatic pathogenic variant carriers were found among the family members of the patients. Although 50% of ARMC5 variant carriers had nonadrenal neoplastic lesions, no LOH or second hit of ARMC5 in the tumor tissues was evident. The ARMC5 variant–positive mutant group showed a higher basal cortisol level than the negative group.

Objectives This study evaluated the prognostic factors for acute exacerbation (AE), including sequential changes in Krebs von den Lungen-6 (KL-6) levels, in rheumatoid arthritis-associated interstitial lung disease (RA-ILD) patients. Methods This was a retrospective observational study. We reviewed 125 patients diagnosed with RA-ILD between 2010 and 2019. We defined ΔKL-6 as the annual variation rate of KL-6 one visit before AE onset (or the last visit). The Cox regression analysis was used for evaluating significant variables associated with AE. We analysed the overall survival and respiratory-related death-free survival. Results Thirty-three patients (26.4%) developed AE during the observation period. The univariate analysis revealed that KL-6 levels at RA-ILD diagnosis [hazard ratio (HR), 1.11; 95% confidence interval (CI), 1.05–1.15; p Conclusion ΔKL-6 can be a prognostic marker for detecting AE in RA-ILD patients.

To analyse the protective effect of different doses of trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis for early severe infections in antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV), considering time-varying changes.In this retrospective observational study, we assessed the protective effect of TMP/SMX within the first 6 months of diagnosis among Japanese patients with AAV. We included 250 consecutive patients with AAV who were admitted to our hospital. The protective effect of TMP/SMX against early severe infections was verified using Cox regression analysis along with potential confounding factors. Cox regression with inverse probability treatment weights for early severe infections was also performed as a sensitivity analysis.Cox regression analysis showed that the reduced TMP/SMX exposure group had a significant protective effect against early severe infections (standard-dose group versus no TMP/SMX group: hazard ratio [HR] 0.393, 95% confidence interval [CI]: 0.139-1.11, p=0.077; reduced-dose group versus no TMP/SMX group: HR 0.418, 95%CI: 0.216-0.807, p=0.009), even when considering time-dependent changes. In the sensitivity analysis, the reduced-dose group still had a significantly lower risk of early severe infections than the no TMP/SMX group (HR = 0.393, 95%CI: 0.177-0.873, p=0.022). During follow-up, 18.0% of the patients discontinued TMP/SMX due to side effects.TMP/SMX is highly effective in preventing severe infections among patients with AAV despite the high incidence of side effects. Further studies are needed to determine the optimal dose of TMP/SMX for preventing severe infections, especially considering renal impairment.

Supplemental Digital Content is available in the text, Recent large observational studies of antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) show that severe infection is a major cause of death and that the majority of infections occur during the early phase of initiating remission-induction therapy. Many risk factors for severe infection have been suggested, but these have been inconsistent. Nevertheless, infectious risk factors in elderly patients with AAV have not been adequately investigated in previous studies. In this retrospective observational study, we examined potential predictors of severe infection within 90 days (early severe infections) after remission-induction therapy in patients with AAV aged 65 years or older. We included 167 consecutive elderly patients with AAV admitted to our hospital. Data from medical history and remission-induction therapy were analyzed for predictive risk factors associated with early severe infections. The relationship between initial doses of corticosteroids and cumulative incidence of severe infections was also analyzed. A multivariate analysis of risk factors for early severe infections was performed using logistic regression analysis. The Kaplan–Meier method was used to estimate the overall survival, and the log-rank test was used to evaluate the differences between patients with and without early severe infections. Gray method was used to compare the cumulative incidence of severe infections in patients who did and did not receive initial high-dose corticosteroids. Logistic regression analysis showed that initial high-dose corticosteroid administration (prednisolone ≥0.8 mg/kg/d) (odds ratio [OR] 3.86, P = .030) and serum creatinine levels at diagnosis ≥1.5 mg/dL (OR 5.13, P = .003) were independent predictors of early severe infection although administration of cyclophosphamide or rituximab was not. The cumulative incidence of severe infections was also significantly higher in patients who received initial high-dose corticosteroids (P = .042), and patients with early severe infections exhibited a high mortality rate within 6 months (P

Background:Acute exacerbation (AE) is a life-threatening complication in connective tissue disease (CTD) associated interstitial lung disease (ILD) (CTD-ILD), including rheumatoid arthritis (RA). Although several risk factors for AE in CTD-ILD have been suggested, these are inconsistent. Krebs von den Lungen-6 (KL-6) is reported as a useful blood marker to detect severe CTD-ILD and RA-ILD, and serum KL-6 levels are significantly higher in patients with AE than in those without AE in RA-ILD patients [1]. However, the predictive value of KL-6 for AE in CTD-ILD or RA-ILD has not been completely confirmed.Objectives:To investigate the predictive factors for AE including initial serum KL-6 levels at RA-ILD onset and sequential changes of KL-6. We also examined the causal relationship between AE and mortality of RA-ILD patients.Methods:We retrospectively reviewed 115 patients with RA-ILD treated in our hospital between 2005 and 2019. Suspected drug-induced pneumonia cases or patients with other coexisting CTD were excluded. Cox regression analyses was used for univariate analysis to detect predictors of AE. Overall survival rate, respiratory-related deaths-free survival rate and AE-free survival rate were analyzed using the Kaplan-Meier method. P < 0.05 was considered statistically significant.Results:Among 115 patients, 29 patients (25.2%) developed AE and 32 patients (27.8%) died. The median follow-up period (IQR) was 57 (25.0-91.5) months, 57.4% were female and the mean age at RA-ILD onset was 72.2 ± 7.9 years old throughout the whole cohort. Among the AE group, methotrexate (MTX), tumor necrosis factor α inhibitor (TNFi) and non TNFi biological-DMARDs were used at AE onset in 10.7%, 0.0%, and 3.6% of patients, respectively. There was a significant difference of serum KL-6 levels at AE onset between AE group and non-AE group (1081.9 ± 624.7 vs 556.1 ± 285.6 U/mL, p < 0.001). Initial serum KL-6 levels at RA-ILD onset in AE group were higher than those in non-AE group, without a significant difference (648.9 ± 325.7 vs 523.7 ± 276.8 U/mL, p = 0.050). The optimal cut-off level of initial serum KL-6 to predict AE was 551 U/mL according to ROC analysis. In univariate analysis, the following factors were significantly associated with AE; usual interstitial pneumonia (UIP) pattern on HRCT at AE onset (Hazard Ratio [HR]: 2.18; 95% confidence interval [CI]: 1.02-4.61; p = 0.045), initial serum KL-6 > 551 U/mL at RA-ILD onset (HR: 2.46; 95%CI: 1.17-5.43; p = 0.018), increasing serum KL-6 levels > 10% before AE onset compared to the previous year (ΔKL-6 > 10%/year) (HR: 4.98; 95%CI: 2.17-11.84; p < 0.001). Initial serum KL-6 > 551 U/mL at RA-ILD onset and ΔKL-6 > 10%/year before AE were also significant prognostic factors for AE when we analyzed only in non-UIP patients (HR: 2.84; 95%CI: 1.15-7.35; p = 0.024, HR: 9.49; 95%CI: 3.02-36.25; p < 0.001, respectively). Conversely, median age at RA-ILD diagnosis, positive ratio of anti-CCP antibody, smoking habits, respiratory comorbidities, SDAI score, and therapeutics at both RA-ILD and AE onset had no significant associations with AE. Patients with initial serum KL-6 > 551 U/mL at RA-ILD onset and ΔKL-6 > 10%/year before AE had a significantly worse AE-free survival rate compared to others (p < 0.001). (Figure 1). Moreover, patients with AE had significantly lower overall survival rate (p < 0.001) and respiratory-related deaths-free survival rate (p < 0.001) than those without AE.Figure 1.KL-6 was measured at RA-ILD onset. ΔKL-6 means the annual variation ratio of KL-6 before AE. The survival curve using the Kaplan Meier method (Log rank test).Conclusion:Serum KL-6 levels at the disease onset and its sequential changes may be able to predict AE in the near future and support the early detection of AE in RA-ILD patients.References:[1]Sarcoidosis Vasc Diffuse Lung Dis. 2016 Oct 7; 33 (3):216-223.Disclosure of Interests:Nozomi Tanaka: None declared, Keisuke Nishimura Speakers bureau: Mitsubishi Tanabe Pharma Corporation. Pfizer Inc. Kyowa Kirin Co., Ltd. Chugai Pharmaceutical Co., Ltd. ONO PHARMACEUTICAL CO., LTD. Japan Blood Products Organization. Kissei Pharmaceutical Co., Ltd. Astellas Pharma Inc. AYUMI Pharmaceutical Corporation. Eisai Co., Ltd. DAIICHI SANKYO COMPANY. Norvartis AG. Bayer AG. Sanofi K.K., Daisuke Waki Speakers bureau: Mitsubishi Tanabe Pharma, AbbVie Inc, eisai Co,. Ltd, ONO PHARMACEUTICAL CO., LTD, Keiichiro Kadoba: None declared, Tomohiro Yoshida: None declared, Hiroyuki Murabe: None declared, Toshihiko Yokota: None declared

Background IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition characterized by tumefactive lesions and, often but not always, elevated serum IgG4 levels [1]. Glucocorticoids (GC) are usually used as induction therapy for IgG4-RD. However, relapse often occurs following GC tapering, and predictors of relapse remain unclear. Objectives To identify predictors of relapse of IgG4-RD after induction therapy. Methods We retrospectively reviewed 57 patients diagnosed with IgG4-RD and treated with GC in our hospital between January 2004 and November 2018. Clinical features at baseline, including organ involvement and blood markers (total hemolytic complement [CH50], its fractions [C3 and C4], IgG4, IgG, IgE, anti-nuclear antibody, rheumatoid factor, C-reactive protein, soluble interleukin-2 receptor, eosinophils), were collected. We divided patients into 2 groups on the basis of clinical features and examined whether they relapsed. In this study, hypocomplementemia was defined as decreased serum C3, C4, or CH50 less than the lower limit of normal. A relapse was defined as any new or worsened state of disease activity that required an escalation in treatment (immunosuppressants and/or GC). The follow-up period was defined as 182 days. Results Forty-three men and 14 women (mean age 68.1 ± 10.9 years) were included. Both serum IgG4 and IgG were measured at baseline in all patients (mean IgG4 798.8 ± 873.1 mg/dL and mean IgG 2874.0 ± 1934.1 mg/dL, respectively). All of the serum C3, C4, and CH50 were measured at baseline in 34/57 patients (mean C3 75.7 ± 33.3 mg/dL; mean C4 14.8 ± 11.5 mg/dL; and mean CH50 37.0 ± 23.1 U/mL). Fifteen patients had at least one episode of hypocomplementemia, and 19 patients did not. Most patients had multiple organ lesions. The details of dominant lesions were as follows: Dacryoadenitis and/or sialadenitis (Mikulicz disease), 36/57 patients (63.2%); biliary or pancreatic lesion, 29/57 (50.1%); retroperitoneal fibrosis, 22/57 (38.6%); and renal lesion 16/57 (28.1%). All patients were given prednisolone and gradually reduced (mean induction dose 31.7 ± 9.8 mg/day). No patients received immunosuppressant as induction therapy. During the follow-up period, 6 patients relapsed, and the dose of prednisolone was increased immediately. Relapsed lesions were as follows: Mikulicz disease, 3/6 patients (50.0%); biliary or pancreatic lesion, 1/6 (16.7%); retroperitoneal fibrosis 1/6 (16.7%); and pulmonary lesion 1/6 (16.7%). Patients with hypocomplementemia had significantly shorter relapse-free survival than those without (p=0.039, Figure 1). Patients with decreased serum C4 or CH50 (less than the lower limit of normal) also had significantly shorter relapse-free survival than those without, but those with decreased serum C3 did not. Such a tendency was not seen in other blood markers (IgG4, IgG, IgE, anti-nuclear antibody, rheumatoid factor, C-reactive protein, soluble interleukin-2 receptor, eosinophils). Conclusion Hypocomplementemia at baseline in patients with decreased serum C4 or CH50 may predict relapse of IgG4-RD after prednisolone therapy. References [1] Stone JH, et al. N Engl J Med2012; 366: 539-51. Disclosure of Interests None declared

BACKGROUND: Thyroid storm (TS) is a life-threatening condition requiring emergency treatment. The reported mortality of TS is 10-20%, but there have not been many large clinical studies regarding the severity and prognosis of TS. The 2017 Guidelines for the Management of Thyroid Storm (The Japan Thyroid Association (JTA) and The Japan Endocrine Society) indicate that there is a significant correlation between TS mortality and the Acute Physiology and Chronic Health Evaluation (APACHE II) score (Odds ratio: 1.15), as well as between TS mortality and the Sequential Organ Failure Assessment (SOFA) score (Odds ratio: 1.33). In this report, we examined which severity score is a prognostic predictor of TS severity, in a comparison between the JTA score and the Burch-Wartofsky point scale (BWPS). CLINICAL CASES: In a retrospective chart review of patients diagnosed and treated at the Kurashiki Central Hospital (Kurashiki City, Japan) from 2005 to 2017, 3361 patients were diagnosed with Graves' disease, but only 5 developed TS (0.14%). TS was defined using the JTA and BWPS criteria; based on the use of either diagnostic criteria, the diagnosis of TS did not differ. Its severity was defined using the SOFA and APACHE II scores. The median age was 56 years [49-77 years]; females comprised 3 of the 5 patients (60%). Only 1 patient experienced a fatal case of TS. All 5 cases met the JTA criteria for definite diagnosis of TS; the median BWPS score was 80 points [55-85 points]. The median SOFA score was 3 points [0-5 points] and the media APACHE II score was 16 points [10-20 points]. The APACHE II score of the fatal case was 20 points, which was the highest among all 5 cases. Among the surviving cases, the periods of treatment in the Intensive Care Unit was less than 3 days. All survival cases were treated with antithyroid drugs, β-blockers, glucocorticoids, and acetaminophen. None of the patients in our report underwent hemodialysis. The APACHE II score is an accurate measure of severity of illness that correlates strongly with patient outcome. In our analysis, there was no difference between the survival cases and the fatal case, with respect to the JTA and BWPS criteria, or the SOFA score. However, the APACHE II score of the fatal case was higher than that of the survival cases. Notably, Aa-DO2/PaO2, arterial blood pH/venous blood HCO3-, and Glasgow Coma Scale were the major factors associated with mortality. CONCLUSION: Our data suggested that there was no difference in the diagnosis of TS, based on the diagnostic criteria of JTA and BWPS. The APACHE II score was helped to estimate the severity of multiple organ dysfunction of TS.

Background:Skeletal muscle is known as one of the organ involvements of primary systemic vasculitis.1,2 Muscle inflammation is detected by magnetic resonance imaging, and necrotizing vasculitis is proved by muscle biopsy.3 As with systemic vasculitis or single organ vasculitis, glucocorticoid (GC) and immunosuppressants are used in its treatment.4 There are not many reports about muscular vasculitis, and its long-term clinical course after initial treatment, including the rates of relapse and mortality, remains unclear.Objectives:To identify the predictors of relapse and mortality in patients with muscular vasculitis, especially focusing on the status of anti-neutrophil cytoplasmic antibody (ANCA).Methods:We retrospectively reviewed patients diagnosed with necrotizing vasculitis with muscle involvements in our hospital between 2004 and 2020. In all cases, muscular vasculitis was identified by muscle biopsy or magnetic resonance imaging. To focus on the clinical features of muscular vasculitis, we excluded patients with such severe organ involvements as cardiovascular, abdominal, cerebral, severe renal, and severe pulmonary involvements. We compared the 5-year cumulative incidence of relapse, the overall survival rate, and the dose of GC over 5 years between the ANCA-positive and ANCA-negative groups. A relapse was defined as any new or worsened state of disease activity requiring an escalation of GC dose. Gray’s method was used for assessing the cumulative incidence of relapse. The log-rank test was used for assessing overall survival. The Mann-Whitney U test was used for assessing the dose of GC. The possible factors for relapse in 5 years in a univariate analysis were selected for a multivariate analysis using the Cox proportional hazards model.Results:Forty-nine patients were enrolled. The median age of onset was 77 (69-82) years and 71.4% were women. There were 30 ANCA-positive patients (90.0% with anti-myeloperoxidase) and 19 ANCA-negative patients. The median age and the number of patients with renal involvements were higher in the ANCA-positive group than in the ANCA-negative group (73.0 ± 9.29 years vs. 79.5 ± 20.28 years, p=0.0062 and 7/30 [23.3%] vs. 0/19 [0.0%], p=0.034, respectively). The Birmingham Vasculitis Activity Score (ver. 3), the induction dose of GC, and the rate of immunosuppressants use were not significantly different between the two groups. During the observational period, 24 patients relapsed. The 5-year cumulative incidence of relapse was significantly higher in the ANCA-positive group than in the ANCA-negative group (p=0.026) (Figure 1). The Cox proportional hazards model revealed that the presence of ANCA was an independent risk factor for relapse (hazard ratio: 3.15; 95% confidence interval 1.06–9.38; p=0.040). During the observational period, 9 patients died (3 died from cancer, 1 from interstitial pneumonia, 1 from cerebral hemorrhage, 1 from infection, and 3 from unknown reasons). The ANCA-positive group exhibited a higher mortality rate than the ANCA-negative group without a statistical significance (p=0.12). The 5-year cumulative dose of GC was larger in the ANCA-positive group than in the ANCA-negative group without a statistical significance (14786 [11246–19138] mg vs. 10088 [7129–12634] mg, p=0.12).Conclusion:In muscular vasculitis, the presence of ANCA is an independent risk factor for long-term relapse. Stratified treatment depending on the ANCA status may reduce the relapse rate and the occurrence of side effects of GC in patients with muscular vasculitis.References:[1]Kitching AR et al. Nat Rev Dis Primers 2020; 6(1): 71.[2]Hernández-Rodríguez J et al. J Autoimmun 2014; 48-49: 84-9.[3]Ushiyama S et al. Rheumatol Int 2020; 40(10): 1667-74.[4]Ganeshanandan LR et al. Semin Arthritis Rheum 2020; 50(3): 503-8.Disclosure of Interests:None declared

Adrenal cortex and medulla are derived from mesoderm and ectoderm, respectively. Mixed corticomedullary tumors (MCMTs), comprising an intimately admixed population of both adrenal cortical cells and pheochromocytes in a single adrenal tumor, are extremely rare and its pathogenesis has remained unknown. Here, we report a case of MCMT whose cells co-expressed cortical and medullary antigens in the same tumor cells.[Case description]A 40-year-old woman was referred to our hospital for investigating Takotsubo cardiomyopathy following resection of uterine fibroids. An abdominal CT scan depicted a 24 mm tumor on her left adrenal gland. Her basal serum ACTH, cortisol levels and urinary cortisol were 13.8 pg/mL, 9.5 μg/dL, and 26.5 μg/day respectively. The cortisol level was normally suppressed by an administration of 1 mg dexamethasone (1.4 μg/dL). Plasma renin activity, aldosterone levels and urinary aldosterone were 15.0 ng/mL/h, 122 pg/mL, and 5.0 μg/day, respectively (with administration history of azosemide). On the other hand, her plasma adrenaline and noradrenaline levels were elevated as high as 177 pg/mL and 536 pg/mL, and urinary metanephrine and normetanephrine were 2.12 mg/day and 1.10 mg/day. A 123I-metaiodobenzylguanidine scan revealed high uptake in the tumor. After adequate adrenergic α-receptor blockage, left adrenalectomy was performed. Her postoperative endocrine and clinical findings were normalized without any further complications.[Pathology] Immunohistochemistry (IHC) revealed the presence of MCMT. Cells morphologically consistent with pheochromocytoma and adrenocortical cells were confirmed by immunostaining of chromogranin A and SF-1, respectively. Chromogranin A-positive medullary-derived and SF-1-positive cortical-derived tumor cells were intermixed in the chimeric fashion. In addition, some tumor cells were positive for both proteins, indicating hybrid nature of the cells. Tumor cells of cortical origin expressed CYP11β1, 3β-HSD, p450c21, and p450c17, but not CYP11β2. Non neoplastic adrenal cortex were atrophic, whereas the glomerulosa was hyperplastic positive for CYP11β2, consistent with diffuse hyperplasia and adrenal medullar unremarkable. [Conclusions:]The adrenal tumor was clinically diagnosed as pheochromocytoma, but the pathological findings did reveal cortisol production in the tumor and aldosterone overproduction in the accompanying cortex. This is the first case of MCMT co-expressing adrenal medullary and cortical antigens in the same tumor cells as hybrid cells.

Rationale: Thrombocytepenia, anasarca, fever, renal insufficiency, and organomegaly (TAFRO) syndrome is a novel disease entity characterized by a constellation of symptoms (thrombocytopenia, anasarca, fever, renal insufficiency, and organomegaly). Here, we describe the development of TAFRO syndrome-like features during the treatment of rheumatoid arthritis with a Janus kinase (JAK) inhibitor. Patient concerns: In this report, a 74-year-old woman treated with a JAK inhibitor (tofacitinib) for rheumatoid arthritis was admitted because of fever and thrombocytopenia. Diagnoses: On laboratory examination, marked thrombocytopenia and elevated creatinine and C-reactive protein levels were present. A computed tomography scan revealed lymphadenopathy, hepato-splenomegaly, and anasarca. A left axillary lymph node biopsy revealed Castleman's disease-like features. These clinical features satisfied the proposed diagnostic criteria for TAFRO syndrome. Since autoimmune disorders should be excluded when diagnosing TAFRO syndrome, it is not strictly correct to diagnose her as TAFRO syndrome. Therefore, we diagnosed her as rheumatoid arthritis complicated by TAFRO syndrome-like features. Interventions: The patient was treated with high-dose glucocorticoid, tacrolimus, eltrombopag, intravenous immunoglobulin, and rituximab. Outcomes: Her condition was refractory to the above-mentioned treatment, and she eventually died because of multi-organ failure 6 months after the first admission. Lessons: TAFRO syndrome-like features can develop during treatment with a JAK inhibitor for rheumatoid arthritis. Patients with autoimmune diseases complicated by TAFRO syndrome-like features can follow a fatal clinical course, and thus, an intensive combined treatment is warranted for such patients, especially in cases refractory to glucocorticoid.

Background:There are several reports that cytomegalovirus (CMV) reactivation resulted in more co-infections affecting survival in rheumatic disease, and CMV reactivation can lead to infections in granulomatosis with polyangiitis patients by inducing CD4+CD28- T cell and depressing naïve T cell populations.1-4Despite this evidence, the prognostic value of CMV reactivation for severe infections in patients with connective tissue disease are still unknown.Objectives:The aim of this study was to examine prognostic factors for severe infection during the early phase of treatment, especially in CMV reactivation, in patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) who received initial high dose corticosteroid therapy (prednisolone > 0.8mg/kg/day).Methods:We analyzed the data of 88 consecutive hospitalized patients newly diagnosed with AAV at our hospital from January 2006 to March 2019 in this retrospective cohort study. There were 32 patients with CMV reactivation during remission induction therapy compared to 56 patients without CMV reactivation. CMV reactivation was defined by the detection of CMV pp65 antigen in blood samples, and CMV positive cells ≥ 5 per 3.0 × 105polymorphonuclear neutrophils (PMNs). The variable for severe infections within 180 days with apvalue < 0.1 in univariate analysis were selected for multivariate analysis using the Cox regression model. The positive predictive value (PPV) and positive likelihood ratio (PLR) of CMV reactivation for subsequent severe infections were also analyzed.Results:Patients with CMV reactivation, compared to those without, had a higher prevalence of MPO-ANCA, renal manifestation and renal impairment at diagnosis, received hemodialysis (HD), higher revised five factor score (FFS), older age, higher Birmingham Vasculitis Activity Score at diagnosis, and higher initial doses of corticosteroids (CS) at baseline. Revised FFS ≥ 2, renal involvement, high initial serum creatinine (≥ 1.5 mg/dl) at diagnosis, received HD, and CMV reactivation were associated with severe infections in the univariate analysis, although receiving cyclophosphamide or rituximab was not. Among these variables, CMV reactivation (Hazard ratio [HR] 3.50; 95% confidence interval [CI]: 1.22-10.10;p= 0.02) and high initial serum creatinine at diagnosis (HR 8.09; 95%CI: 2.00-32.73;p< 0.01) were independent risk factors for severe infections within 180 days. (Table 1) The PPV and PLR of CMV reactivation for subsequent severe infections were 35% and 1.91. When including higher initial serum creatinine, PPV and PLR for subsequent severe infections was 67% and 7.26.Table 1.Cox regression analysis for severe infections within 180 days.Univariate analysisMultivariate analysisPotential prognostic factorsHR (95% CI)P valueHR (95% CI)P valueAge ≥ 651.36 (0.48-3.71)0.580Male1.23 (0.50-3.04)0.648Past history of lung disease0.39 (0.11-1.36)0.140Past history of diabetes mellitus0.64 (0.15-2.77)0.550Lung involvement1.76 (0.67-4.62)0.254Renal involvement†3.68 (1.22-11.10)0.021Serum Cr ≥ 1.5 at diagnosis9.50 (3.40-26.49)< 0.0018.09 (2.00-32.73)0.003Hemodialysis4.85 (1.73-13.54)0.0030.96 (0.31-2.97)0.950BVAS ≥ 201.50 (0.59-3.81)0.393Revised FFS ≥ 24.40 (1.28-15.13)0.0180.83 (0.16-4.27)0.818MPSL pulse therapy1.16 (0.47-2.86)0.746Received CYC or RTX1.54 (0.55-4.27)0.409CMV reactivation5.10 (1.93-13.48)0.0013.50 (1.22-10.06)0.020† “Renal involvement” was excluded in the multivariate analysis to avoid multicollinearity.Conclusion:Our study shows that there should be focus on subsequent severe infections when CMV reactivation is detected during early phase of treatment, especially in renal-impaired patients with ANCA-associated vasculitis.References:[1]Gardiner BJ et al. Rheumatol Int. 2019;39:1229-40[2]Hung M et al. J Microbiol Immunol Infect. 2019;52:114-21.[3]Hanaoka R et al. Mod Rheumatol. 2012;22:438-45.[4]Morgan MD et al. Arthritis Rheum. 2011;63:2127-37.Disclosure of Interests:Daisuke Waki Speakers bureau: Mitsubishi Tanabe Pharma, AbbVie Inc, eisai Co,. Ltd, ONO PHARMACEUTICAL CO., LTD,, Keisuke Nishimura Speakers bureau: Mitsubishi Tanabe Pharma Corporation. Pfizer Inc. Kyowa Kirin Co., Ltd. Chugai Pharmaceutical Co., Ltd. ONO PHARMACEUTICAL CO., LTD. Japan Blood Products Organization. Kissei Pharmaceutical Co., Ltd. Astellas Pharma Inc. AYUMI Pharmaceutical Corporation. Eisai Co., Ltd. DAIICHI SANKYO COMPANY. Norvartis AG. Bayer AG. Sanofi K.K., Tomohiro Yoshida: None declared, Keiichiro Kadoba: None declared, Nozomi Tanaka: None declared, Hiroyuki Murabe: None declared, Toshihiko Yokota: None declared

We aimed to investigate the efficacy of plasma exchange on severe anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). Of 182 patients with AAV in our hospital, 12 patients with life-threatening organ damage (rapidly progressive glomerulonephritis and/or diffuse alveolar hemorrhage) underwent centrifuge-based therapeutic plasma exchange and immunosuppressive therapy. Twenty-four patients matched for age, serum creatinine, and severity of vasculitis, who received high-dose glucocorticoids with or without immunosuppressants, were included in the nonplasma exchange group. Renal survival rate at 2 years from induction treatment was not significantly different between the plasma and nonplasma exchange groups (P = 0.524). Mortality rate at 5 years from induction treatment was not significantly different between the plasma and nonplasma exchange groups (P = 0.631). In this retrospective study, we could not show the significant differences in the renal survival rate and survival rate between the two groups.

Prophet of Pit-1 (Prop-1), which is a paired-like homeodomain transcription factor, is capable of binding to sites in an early enhancer of the Pit-1 gene and regulating its expression. According to a previous report, Prop-1 messenger RNA (mRNA) is expressed in the developing pituitary gland before Pit-1 mRNA expression and maximum expression are observed at e 12.0. After e 14.5, Prop-1 mRNA expression rapidly decreases, and only trace amounts of mRNA are detectable in adult mouse pituitary. Human Pit-1 is expressed considerably, not only in normal adult pituitary but also in pituitary adenomas, so we studied human Prop-1 gene expression in adult pituitary and pituitary adenomas. We also cloned human Prop-1 complementary DNA (cDNA) and sequenced the Prop-1 cDNAs in pituitary adenomas. The amino acid sequence of human Prop-1 cDNA that we cloned was identical to that of the previously reported sequence, except Thr substituted at codon 142 instead of Ala. This amino acid substitution is considered to be a pol...

A 48-year-old female presented with acromegaly, amenorrhea and hyperthyroidism associated with high serum free T4 levels and measurable TSH concentrations. The administration of GHRH induced significant increases in GH, PRL and TSH. Conversely, intravenous infusion of dopamine or oral administration of bromocriptine effectively inhibited GH, PRL and TSH secretion. Serum alpha-subunit levels were neither affected by GHRH, dopamine nor bromocriptine. Transsphenoidal surgery was performed and immunostaining of the tissue showed that the adenoma cells were positive for GH, PRL or TSH. The patient was treated with bromocriptine at a daily oral dose of 10 mg after surgery. Serum TSH were initially suppressed but returned within reference intervals with persistent normalized free T4 levels. Serum PRL became undetectable and GH levels were stable around 6 ng/ml except the periods of poor drug compliance, when serum TSH, GH and PRL levels rose considerably. The patient was followed-up for 10 years without any change in the residual adenoma tissues as detected by magnetic resonance imaging. These findings suggest that long-term bromocriptine therapy is effective in treating the hypersecretory state of a plurihormonal adenoma secreting TSH, GH and PRL.

PATIENT: Male, 66. FINAL DIAGNOSIS: Hypercalcemic crisis. SYMPTOMS: Near drowning state. MEDICATION: - CLINICAL PROCEDURE: - SPECIALTY: Critical care medicine. OBJECTIVE: Challenging differential diagnosis. BACKGROUND: Hypercalcemic crisis, generally caused by malignancy or primary hyperparathyroidism, is a life-threatening emergency that can result in multi-organ failure. Lowering the patient's calcium level immediately and determining the correct etiology are essential. CASE REPORT: We report a case of hypercalcemic crisis with a novel etiology. A 66-year-old male presented to the emergency room in cardiac arrest with a ventricular arrhythmia after being discovered submerged in an indoor public bath. He underwent cardioversion and was emergently intubated. Computed tomography showed bilateral pulmonary edema, suspected from water aspiration. Laboratory data revealed severe hypercalcemia and mild hypernatremia. Following three days of continuous hemodiafiltration, serum Ca decreased to and remained within normal limits. We concluded the etiology of hypercalcemia was absorption of Ca resulting from aspirated water. CONCLUSIONS: Near drowning can be a cause of hypercalcemic crisis. For cases of near drowning, it is important to investigate the source of the aspirated water and consider electrolyte abnormalities in the diagnosis. Language: en

The expression of neurotrophin-3 (NT-3) in skeletal muscles was measured in rats with streptozotocin (STZ)-induced diabetes using Northern blot analysis. At 6 weeks after STZ induction of diabetes, the NT-3 mRNA level in the quadriceps and gastrocnemius muscles was decreased by 45 and 77%, respectively, compared with that in age-matched controls. Since NT-3 is considered to be essential for the maintenance of spinal proprioceptive afferent neurons, decreased NT-3 expression in target tissues would impair the integrity of afferent neurons and might be an earlier marker in the sensory neuronal damage observed in diabetes mellitus.

The dynamics of GH secretion were investigated in an acromegalic patient with Graves' disease during treatment with antithyroid drugs and radioactive iodine. The mean (+/- SE) basal plasma GH levels were 16.5 +/- 0.9 and 7.8 +/- 0.7 micrograms/L during the hyperthyroid and euthyroid states, respectively. There was a positive correlation (r = 0.902) between basal GH and free T4 levels. Twenty-four-hour plasma GH and urinary GH excretion both increased during the thyrotoxic state. Intravenous administration of TRH induced a marked increase in plasma GH levels during euthyroidism and a modest increase when the patient was hyperthyroid, whereas GH release induced by GH-releasing hormone was not altered by thyroid status. These findings suggest that hyperthyroidism stimulated spontaneous GH secretion from the pituitary adenoma, but inhibited the stimulating effect of TRH.

Adrenomedullin (AM), a potent vasorelaxing, natriuretic and cell growth-modulating peptide, is thought to act as an autocrine/paracrine regulator in renal glomeruli and tubules. AM receptors comprise the calcitonin receptor-like receptor (CRLR) and a family of receptor-activity-modifying proteins (RAMPs 1-3); however, the pathophysiological role of AM and its receptor system in the kidney remains to be clarified. We examined the regulation of their expression in a rat model of renal injury and found that RAMP1, RAMP2 and CRLR expressions were markedly upregulated upon induction of fibrosis during obstructive nephropathy. Since AM exerts potent antiproliferative effects in various cell types, upregulation of the AM receptor system may play important roles in modulating the progression of renal diseases.

Octreotide usually induces long-acting inhibition of GH secretion without rebound hypersecretion. We report a patient with acromegaly who showed rebound elevation of GH and insulin-like growth factor-1 (IGF-1) after octreotide withdrawal. The patient responded remarkably to octreotide therapy with normalization of GH and IGF-1 and shrinkage of pituitary macroadenoma. Octreotide therapy was stopped when he developed liver dysfunction. GH and IGF-1 were markedly elevated for two weeks after cessation of octreotide.

Prophet of Pit-1 (Prop-1), which is a paired-like homeodomain transcription factor, is capable of binding to sites in an early enhancer of the Pit-1 gene and regulating its expression. As human Pit-1 is expressed considerably in pituitary adenomas, we studied human Prop-1 gene expression in pituitary adenomas. We also sequenced the Prop-1 cDNAs in pituitary adenomas. Human Prop-1 transcript was detected in all pituitary adenomas examined by RT-PCR analysis. The expression of human Prop-1 in pituitary adenomas was confirmed by in situ hybridization in one of the GH-producing adenomas. The sequence analysis of human Prop-1 cDNAs in these pituitary adenomas revealed that there were no mutations except 5 silent nucleic acid substitutions, suggesting that mutations of Prop-1 gene do not represent a frequent mechanism of human pituitary tumorigenesis.

Five hyperthyroid patients with TSH-secreting pituitary adenoma were treated with octreotide. Acute administration of octreotide decreased plasma TSH levels in all patients (mean decrease, 50.6 +/- 14%). Treatment with octreotide (25-300 microg/day) for 2-360 weeks resulted in reductions in plasma TSH and alpha-subunit levels in three patients, and serum free thyroxine levels were normalized with concomitant clinical improvements such as disappearance of excessive sweating, tachycardia and finger tremors. In two patients, plasma TSH and free thyroxine levels were initially decreased, but tachyphylaxis occurred 3 and 10 weeks after the initiation of therapy. Mild to marked shrinkage of the tumor was observed 2-50 weeks later in four patients. Shrinkage of the tumor seems to be reversible in one case. Frequent bowel movements and epigastric discomfort occurred in two patient. Somatostatin receptor subtype 2 (sst2) mRNAs were detected in two adenoma tissues studied by RT-PCR. Long-term treatment with octreotide is effective in controlling hyperthyroidism and tumor growth in patients with TSH-secreting pituitary adenoma.

Acute muscle pain with stiffness developed in a patient with latent hypothyroidism after administration of clofibrate. Serum creatine kinase (CK), aspartate aminotransferase, and lactate dehydrogenase were markedly elevated, but returned to normal one and a half months after the discontinuation of clofibrate. Clofibrate challenge (750 mg/day) for three days caused muscle pain and an elevation in serum CK. Hypothyroidism may be a predisposing factor in the development of clofibrate-induced myopathy.

McCune-Albright syndrome (MAS) is clinically characterized by polyostotic fibrous dysplasia, cafe au lait pigmentation of the skin and multiple endocrinopathies. Recently activating mutations of codon 201 in the gene encoding Gs alpha have been found in affected tissues in MAS. Herein we report a case of acromegaly associated with multiple bone cysts and skin pigmentation in a 47-year-old women. She had suffered a history of aortitis syndrome. The DNA sequence indicated that a Cys201 for Arg201 substitution was found in the GH secreting pituitary adenoma tissue but not in peripheral mononuclear cells. We speculate that the patient has a possible variant from of MAS characterized by multiple bone lesions skin pigmentation and GH-secreting pituitary adenoma.

The expression of somatostatin receptor (SSTR) subtypes and relative abundance of SSTR2 mRNA were examined in 18 pituitary adenomas using the reverse transcription-polymerase chain reaction (RT-PCR) method. SSTR1 and SSTR2 were expressed in all pituitary adenomas examined. Six of 9 somatotroph adenomas, 1 of 4 lactotroph adenomas and 1 of 2 thyrotroph adenomas also expressed SSTR5. SSTR3 and SSTR4 mRNAs were detected in 1 and 2 cases of somatotroph adenoma, respectively. SSTR2 mRNA expression was quantified by comparison with the PCR cycle-dependent amplification of beta-actin or cyclophilin. The relative abundance of SSTR2 mRNA varied greatly among adenomas with more than a 1000-fold difference. SSTR2 mRNAs in lactotroph adenomas were less abundant (P < 0.01) than those in somatotroph adenomas. No significant correlation was found between the relative abundance of SSTR2 mRNA levels and GH sensitivity to octreotide administration. However, one of the thyrotroph adenomas exhibited marked shrinkage in tumor size after octreotide therapy, in which SSTR2 mRNA was the most abundant among the adenomas examined. GH sensitivity to octreotide was not significantly different between SSTR5 mRNA positive and negative adenomas. In conclusion, SSTR2 mRNA levels varied greatly among pituitary adenomas but were not correlated with GH sensitivity to octreotide. Further investigations of functional SSTR subtype proteins and of postreceptor signal transductions are required to clarify the molecular mechanisms of octreotide action.

Cardiac metastasis of thyroid carcinoma is extremely rare. We treated a case of anaplastic thyroid carcinoma with prominent cardiac metastasis. The 61-year-old male was admitted because of high fever. Investigations revealed a cardiac mass and anaplastic thyroid carcinoma. Resection of the cardiac mass revealed that it was metastasis from the thyroid carcinoma. After 4 months, he died in spite of intensive therapy. Marked leukocytosis was observed during the clinical course, and a concomitant increase of granulocyte macrophage-colony stimulating factor (GM-CSF) level was demonstrated in the sera. It was suggested that the high GM-CSF level in serum contributed to leukocytosis.