Safety and effectiveness of abatacept in Japanese non-elderly and elderly patients with rheumatoid arthritis in an all-cases post-marketing surveillance.

Objectives: To investigate the safety, effectiveness, and risk-benefit balance of intravenous abatacept (ABA) in non-elderly (<65 years: NEG) and elderly (≥65 years: EG) rheumatoid arthritis patients. Methods: This sub-analysis of an all-cases postmarketing surveillance in Japan assessed safety in all enrolled patients and effectiveness in those with Disease Activity Score 28 based on C-reactive protein (DAS28-CRP) measurements at ≥2 time points including baseline. Risk-benefit was evaluated based on infections and DAS28-CRP improvement >1.2. Results: The NEG and EG of the safety analysis set comprised 2,170 and 1,712 patients, respectively; corresponding 6-month ABA retention rates were 80.2% and 77.1%. The NEG had fewer adverse drug reactions (14.5% vs. 17.2%, p = .021) and infections (4.8% vs. 7.2%, p = .002) than the EG. DAS28-CRP changed similarly between groups. The proportion of patients with low-risk/high-benefit and high-risk/low-benefit were 33.1% and 6.9% (NEG) and 29.7% and 9.0% (EG). Low-risk/high-benefit patients were younger, had shorter disease duration and fewer comorbidities, and were with less use of oral glucocorticoid and prior biologics, more use of methotrexate and higher DAS28-CRP than high-risk/low-benefit patients at baseline. Conclusion: ABA was well tolerated and similarly efficacious in the EG and NEG. Identification of factors related to low-risk/high-benefit may aid appropriate patient selection.

Incidence of hepatitis B virus reactivation in patients with resolved infection on immunosuppressive therapy for rheumatic disease: a multicentre, prospective, observational study in Japan.

BACKGROUND: Although the reactivation of hepatitis B virus (HBV) is recognised as a serious complication in patients with rheumatic disease (RD) receiving immunosuppressive drugs (ISDs), the incidence and risk factors for reactivation remain controversial. OBJECTIVES: To investigate the incidence and risk factors for HBV reactivation in patients with RD. METHODS: We performed a multicentre, observational, prospective study over 2 years in patients with resolved HBV infection. Patients with RD treated with a dose of ≥5 mg/day prednisolone and/or synthetic or biological ISDs with negative HB virus surface antigen and positive anti-HB virus surface antibody (HBsAb) and/or anti-HB virus core antibody (HBcAb) were enrolled. Quantitative HBV DNA results and related data were regularly recorded. RESULTS: Among 1042 patients, including 959 with rheumatoid arthritis, HBV DNA was detected in 35 (1.93/100 person-years), with >2.1 log copies/mL observed in 10 patients (0.55/100 person-years). None of the reactivated patients, including seven treated with a nucleic acid analogue, showed overt hepatitis. Low HBsAb titres and advanced age seemed to be risk factors for HBV reactivation; however, reactivation was observed in three patients with positive HBsAb and negative HBcAb test results. The risk of reactivation was lower with methotrexate but higher with prednisolone among the different types of ISDs. The intervals from the start of ISD to reactivation were relatively long (3-182 months; median, 66 months). CONCLUSIONS: The incidence of HBV reactivation with ISD use was 1.93/100 person-years in patients with RD with resolved HBV infection. No overt hepatitis was observed in the reactivated patients.

Postmarketing surveillance of the safety and effectiveness of abatacept in Japanese patients with rheumatoid arthritis.

OBJECTIVE: To perform a postmarketing surveillance study evaluating the safety and effectiveness of abatacept in Japanese patients with rheumatoid arthritis (RA). METHODS: Safety and effectiveness data were collected for all RA patients (at 772 sites) treated with intravenous abatacept between September 2010 and June 2011. Patients were treated by the approved dosing regimen according to the package insert. Treatment effectiveness was evaluated at baseline and at weeks 4, 12, and 24 using Disease Activity Score 28 (DAS28) according to erythrocyte sedimentation rate or serum C-reactive protein concentrations. RESULTS: Overall, 3882 and 3016 abatacept-naïve RA patients were included in safety and effectiveness analyses, respectively. Adverse drug reactions (ADRs) were reported for 15.66% of patients and serious ADRs were detected for 2.52% of patients. The incidence of serious infections was 1.03% and these were mainly attributed to different types of bacterial pneumonia. Disease activity improved significantly over 6 months. Separate multivariate analysis identified predictors of severe ADR, and severe infections and factors predictive of clinically meaningful DAS28 improvement after 6 months of treatment with abatacept. CONCLUSIONS: Abatacept was efficacious and well tolerated in a clinical setting. No new safety concerns were detected.

Trend of patient characteristics and its impact on the response to adalimumab in patients with rheumatoid arthritis: post hoc time-course analysis of an all-case PMS in Japan.

OBJECTIVES: To investigate the relationship between changes in patient characteristics over time and the effectiveness and safety of adalimumab in the treatment of rheumatoid arthritis (RA) in clinical practice. METHODS: Patients enrolled in the post-marketing registry study in Japan were divided into 5 subgroups based on the time adalimumab treatment was initiated. Demographic and baseline characteristics and responses to adalimumab were compared among the 5 subgroups to detect any time-course trend. Multiple logistic regression analysis was performed to identify characteristics that were significantly associated with the effectiveness or safety of adalimumab and to estimate response rates and the incidence of adverse drug reactions in individual subgroups. RESULTS: During the study period, patient characteristics changed significantly over time, in particular with regard to prior biologic use and concomitant methotrexate therapy. There was a significant trend toward higher response rates and lower incidence of infections and injection-site reactions in patients initiating adalimumab later in the study. Patient characteristics, such as concomitant methotrexate therapy and early stage RA, were significant predictors of the effectiveness and safety of adalimumab. CONCLUSIONS: Patient characteristics have changed since adalimumab became available for the treatment of RA; several of these characteristics were significant predictors of adalimumab effectiveness and safety.

Safety and effectiveness of adalimumab in Japanese rheumatoid arthritis patients: postmarketing surveillance report of 7740 patients.

OBJECTIVES: To confirm the safety and effectiveness of adalimumab and to evaluate the influence of the concomitant use of methotrexate (MTX). METHODS: Postmarketing surveillance of 7740 Japanese rheumatoid arthritis (RA) patients was performed. All patients who received adalimumab in the registration period were followed for 28 weeks after starting treatment for safety and 24 weeks for effectiveness. Effectiveness was measured by duration of morning stiffness, swollen and tender joint counts (28 joints), patient global assessment of disease activity, erythrocyte sedimentation rate and serum C-reactive protein. RESULTS: Comparable rates of adverse drug reactions (ADRs) were reported in this study and in the interim analysis. Age, pulmonary disease history or comorbidity, co-existing diabetes mellitus, concomitant MTX at doses of > 8 mg/week and concomitant glucocorticoids at doses of > 5 mg/day were risk factors for infections. All mean values of effectiveness measurements improved. Relatively lower disease activity at baseline, biologic-naïve, concomitant MTX use and early RA stage/low functional class were background factors contributing to the effectiveness. The combination of adalimumab with MTX improved the response to adalimumab treatment. CONCLUSION: Adalimumab, especially with concomitant use of MTX, provided significant improvement in disease activity, without any unexpected ADRs in Japanese RA patients.

Cure of Fingertip Necrosis after Median Nerve Block Application in Two Cases of Definite and Probable Systemic Sclerosis.

One patient with systemic sclerosis with index fingertip necrosis and another with probable systemic sclerosis with index and middle fingertip impending necrosis were successfully treated with ultrasound-guided median nerve block application on the affected side. The nailfold temperatures of the affected fingers measured using thermography were below 25°C. Immediately after application, the temperature increased substantially. After repeated applications, the mean basal temperature on the affected side increased by 3.6°C in Case 1 and by 5.9°C in Case 2. Peripheral nerve block can be a basic treatment for fingertip necrosis. The thermographical observation of the extent and region in which the temperature increased is novel.

Ibuprofen Would Be the First-Line Nonsteroidal Anti-inflammatory Drug for Polymyalgia Rheumatica: A Case Series of Five Patients.

The primary treatment of choice for polymyalgia rheumatica (PMR) is corticosteroids, which are better avoided for elderly patients susceptible to PMR. The cases of five patients cured with only a small dosage of 600 mg/day ibuprofen without steroids or methotrexate are reported. Their clinical features were compared with those of the 26 PMR patients who had steroids and/or methotrexate in addition to ibuprofen. PMR was diagnosed based on the 2015 EULAR/ACR criteria. They were all females aged 73-80. They all had no giant cell arteritis or autoantibodies. Nonsteroidal anti-inflammatory drugs (NSAIDs) other than ibuprofen had not worked in four cases; for the one, ibuprofen was the first NSAID. Their serum CRP levels were 1.57-12.8 mg/dL at ibuprofen introduction. Colchicine was co-administered in two patients. At the next visit three to seven days after ibuprofen introduction, they all showed a clear recovery with a CRP level decrease. Ibuprofen tapering was started within three months, and no relapse was until two to five years' follow-up. Comparison with the 26 patients who had additional steroid and/or methotrexate showed that the disease duration until ibuprofen introduction was statistically significantly shorter in the five patients (1.40±0.65 vs 3.28±2.98 months). Ibuprofen would be the first-line drug for PMR, and its earliest use would be beneficial.

Cut-off levels of salivary beta2-microglobulin and sodium differentiating patients with Sjögren's syndrome from those without it and healthy controls.

OBJECTIVES: For the diagnosis of Sjögren's syndrome (SS), cut-off levels of ß2-microglobulin (ß2MG) and sodium (Na+) in unstimulated whole saliva have not yet been shown. We aimed to determine the cut-off levels of salivary ß2MG and Na+ which differentiate SS patients from non-SS patients and healthy controls. METHODS: Seventy-one patients of primary SS (pSS, 69 females/2 males, 60.0±16.8 years old), 50 of secondary SS (sSS, 49/1, 55.8±17.4), 54 of connective tissue diseases other than SS (non-SS-CTD, 43/11, 60.0±16.0), and 75 healthy volunteers (HC, 43/32, 50.7±15.6) were included. Unstimulated whole saliva were examined for levels of ß2MG, Na+, potassium (K+), and chloride (Cl-). Receiver-operating characteristic curve analysis was carried out. RESULTS: ß2MG, Na+, and Cl- levels in the SS group (pSS and sSS) were significantly higher than those in the non-SS group (non-SS-CTD and HC). The salivary ß2MG level was 5.3±4.6 mg/L in pSS, 5.1±2.0 in sSS, 2.5±2.1 in non-SS-CTD, and 1.2±0.7 in HC, respectively. The Na+ level was 39.2±25.2 mEq/L, 36.4±26.1, 19.6±16.8, and 16.5±7.3, and the Cl- level was 51.1±25.0, 47.8±24.3, 32.1±16.6, and 27.0±7.9 in the same order. The K+ level in the SS group was significantly higher than that in HC. The optimal cut-off ß2 MG and Na+ levels that differentiate the SS group from the non-SS group were 2.3 mg/L and 23 mEq/L. CONCLUSIONS: Salivary ß2MG and Na+ levels are useful markers for differentiating SS patients from non-SS-CTD patients and HC.

Anti-SS-A (Ro) antibody is positively associated with steroid-induced psychiatric events in systemic lupus erythematosus patients.

Forty-five systemic lupus erythematosus (SLE) patients who had steroid at a prednisolone dose of 0.8 mg/kg/day or more were retrospectively studied for psychiatric events that developed after the therapy. Simple insomnia was excluded. Their age, sex, dose, and duration of steroid, autoantibodies, and prophylactic heparin use were examined. Seventeen patients (female/male: 16/1, 36.7 ± 10.7 years old) developed psychiatric events 18.2 ± 10.2 days after steroid start, whereas 28 patients (27/1, 37.9 ± 13.1) did not. Anti-SS-A (Ro) antibody was more prevalent in patients with the events (15/17 vs. 14/28, p = 0.009). When heparin was administered concurrently with steroid, psychiatric events developed less frequently either in all of the patients (2/17 vs. 11/28, p = 0.048) or in patients positive for the anti-SS-A antibody (2/15 vs. 7/14, p = 0.041). SLE patients positive for the anti-SS-A (Ro) antibody would much more likely develop psychiatric events after a substantial-dose steroid therapy, and a concurrent prophylactic heparin administration might reduce the risk.

Safety and effectiveness responses to etanercept for rheumatoid arthritis in Japan: a sub-analysis of a post-marketing surveillance study focusing on the duration of rheumatoid arthritis.

The aim is to investigate the relationship of duration of rheumatoid arthritis (RA) with safety and effectiveness of etanercept (ETN) in Japan. Post-marketing surveillance data for 7,099 patients treated with ETN were analyzed. Baseline characteristics, treatment effectiveness, incidence of adverse events (AEs), and serious AEs (SAEs) in relation to duration of RA were studied. At baseline, patients with RA for longer duration were older, weighed less, had more comorbidities, allergies, and corticosteroid use, but smoked less and had less morning stiffness. By 2-5 years with RA, more than half of the patients had advanced to Steinbrocker radiographic stage III or IV. Methotrexate (MTX) was the most commonly used pre-treatment disease-modifying antirheumatic drug; however, concomitant MTX use and its dose were lower among patients with longer duration of RA. Remission rates (26.6%) were greatest among patients having RA for <2 years. Less AEs and SAEs were observed among patients with shorter duration of RA. These results suggest that RA treatment in Japan in the era pre-biologics may not have been adequate to control disease activity and prevent joint destruction. Patients with shorter duration of RA may have better physical status which allows the opportunity to treat more intensively putting a higher percentage of patients in remission and possibly decreasing exposure to SAEs.

Safety and effectiveness of switching from infliximab to etanercept in patients with rheumatoid arthritis: results from a large Japanese postmarketing surveillance study.

Finding an effective treatment strategy for rheumatoid arthritis (RA) patients who have not benefited from previous tumor necrosis factor-α antagonist treatment is important for minimizing RA disease activity and improving patient outcomes. The aim of this study was to compare the safety and effectiveness of etanercept in patients with and without infliximab (IFX) treatment experience. Patients (n = 7,099) from a large postmarketing observational study of etanercept use in Japan were divided into 2 cohorts based on previous IFX use (pre-IFX and non-IFX). Baseline characteristics were assessed in each cohort. Adverse events (AEs) and European League Against Rheumatism (EULAR) responses were monitored every 4 weeks for 24 weeks. At baseline, pre-IFX patients were younger and had fewer comorbidities and a shorter RA duration than non-IFX patients. During the study, pre-IFX patients received concomitant methotrexate more often than non-IFX patients. The incidence of AEs and serious AEs were significantly lower in pre-IFX patients, as was the percentage of patients who discontinued treatment. Both cohorts had significant improvement (P < 0.001) in EULAR responses at the end of the treatment period. This study demonstrated that etanercept was effective and well tolerated in active RA patients with and without prior IFX treatment.

Eleven cases of angioedema with eosinophilia treated in a single hospital in Japan.

BACKGROUND: Angioedema with eosinophilia (AE) is mostly reported in Japanese patients, and only as case reports. In this study, we aimed to determine how prevalent AE cases appear, the characteristic features and the course of AE, and to evaluate whether corticosteroid therapy for AE is necessary or not. METHODS: The patients whose blood samples showed an eosinophil count of ≥2,000/µL, among the samples tested for blood cell counts and differential counts between January 2006 and December 2010, in Japanese Red Cross Medical Center, were firstly included. Among these, patients with AE were extracted. RESULTS: All of the 11 patients were Japanese young females. One patient with arthralgia showed radioisotope accumulation in the joints by bone scintigraphy. The peak peripheral blood eosinophil count was 7,839 ± 6,008 (2,130-23,170)/µL after visiting our hospital. An increase in white blood cell count was only due to an increase in eosinophil count. Serum C-reactive protein and IgE levels remained almost normal. Peripheral blood eosinophil count decreased steadily for 8 weeks, regardless of corticosteroid use. Edema in all of the patients and arthralgia in 6 patients improved within 12 weeks. As far as followed, none of the patients had a recurrence of AE. CONCLUSIONS: AE developed in Japanese young females and likely showed a single course. In AE, the count of eosinophil of 104/µL was observed. Only eosinophil count increased among leukocyte series. Serum C-reactive protein and IgE levels remained almost normal. The eosinophil count in AE patients will return to the normal level within 8 weeks even without corticosteroid therapy.

Safety and effectiveness of adalimumab in Japanese rheumatoid arthritis patients: postmarketing surveillance report of the first 3,000 patients.

This interim analysis of postmarketing surveillance data for adalimumab-treated rheumatoid arthritis (RA) patients summarizes safety and effectiveness during the first 24 weeks of therapy for the first 3,000 patients treated in Japan (June 2008-December 2009). Patient eligibility for antitumor necrosis factor therapy was based on the Japanese College of Rheumatology treatment guidelines and Japanese labeling. All patients were screened for tuberculosis. Approximately 50% of the population was biologic naïve, 66% received concomitant methotrexate (MTX), and 72% received concomitant glucocorticoids. The overall incidence rate of adverse events was 31% (5.5% serious) and that of adverse drug reactions (ADRs) was 27% (4.1% serious). Incidence rates of ADRs and serious ADRs were similar regardless of prior biologic therapy or concomitant MTX use but were significantly higher in patients receiving glucocorticoids compared with those not receiving glucocorticoids. Bacterial/bronchial pneumonia occurred in 1.2% of patients; interstitial pneumonia, 0.6%; Pneumocystis jirovecii pneumonia, 0.3%; tuberculosis, 0.13%; and administration-site reactions, 6.1%. Mean 28-joint Disease Activity Scores decreased significantly after 24 weeks from 5.29 to 3.91. All subgroups showed significant improvement, particularly the biologic-naïve patients receiving concomitant MTX. No new safety concerns were identified. ADR Incidence rates were similar to those of other biologic agents approved for RA.

Search of official nationwide database in Japan for adverse events associated with disease-modifying antirheumatic drug therapies: focus on therapies in combination with methotrexate.

BACKGROUND: Disease-modifying antirheumatic drugs (DMARDs) are essential for rheumatoid arthritis (RA) therapy. The adverse events (AEs) evaluation should focus on that methotrexate (MTX) is frequently prescribed in combination with others (combination MTX). METHODS: A search of the website of the official Japanese Agency for AEs, including lymphoproliferative disease (LPD), cytopenia, interstitial pneumonia, infectious pneumonia other than Pneumocystis jirovecii pneumonia (PCP) (i-Pn), and PCP, associated with MTX, tacrolimus, adalimumab, tocilizumab, and abatacept therapies reported from 2014 to 2016 was performed. Number of each AE cases and its ratio to total number of AEs cases were examined. Combination MTX was checked for RA cases. RESULTS: A total of 8874 cases were listed. In 3955 MTX cases, LPD was most frequent (36.4%). In any of the other four DMARDs cases, i-Pn was most frequent (4.2 ~ 15.3%); PCP cases showed most frequent combination MTX (94.4%). In total, including cases reported for MTX therapy, 98.2% of LPD and 97.6% of PCP cases had MTX, and less than 90% of the other AEs cases had MTX. CONCLUSION: LPD was by far the most frequent AE associated with MTX therapy. PCP was strongly associated with combination MTX. For any of the other four DMARDs, i-Pn was most frequent.

Habitual Hot-Tub Bathing and Cardiovascular Risk Factors in Patients With Type 2 Diabetes Mellitus: A Cross-Sectional Study.

Background: Several studies suggested that heat therapy, including sauna or hot-tub bathing, was associated with improved glycemia and other risk factors for cardiovascular diseases. This study aimed to assess the influences of the habit of hot-tub bathing on cardiovascular risk factors in patients with type 2 diabetes in a real-world setting. Methods: In this cross-sectional study, we enrolled the patients with type 2 diabetes who regularly visited the outpatient clinic between October 2018 and March 2019. We obtained the information on the habit of hot-tub bathing by using a self-reported questionnaire. The results of anthropometric measurements, blood tests and medications were obtained from the medical charts. We divided the patients into three groups according to the frequency of hot-tub bathing as follows; group 1: ≥ 4 times a week, group 2: < 4 times a week, ≥ 1 time a week, group 3: < 1 time a week. The biomarkers were compared among the groups by one-way analysis of variance. Multiple linear regression analyses were performed to adjust for confounding variables. Results: We enrolled 1,297 patients. There were significant differences in body mass index (group1: 25.5 ± 5.0, group 2: 26.0 ± 5.4, group 3: 26.7 ± 6.0, P = 0.025), diastolic blood pressure (73 ± 12, 75 ± 12, 77 ± 13, P = 0.001) and hemoglobin A1c (7.10 ± 0.97, 7.20 ± 1.11, 7.36 ± 1.67, P = 0.012). Multiple regression analysis revealed that the frequency of hot-tub bathing was a significant determinant of hemoglobin A1c, body mass index and diastolic blood pressure. Conclusions: In this real-world study, habitual hot-tub bathing was associated with slight improvements in glycemia, obesity and diastolic blood pressure, and thus, can be a possible lifestyle intervention in patients with type 2 diabetes.

Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients.

OBJECTIVE: An interim analysis of an all-patient postmarketing surveillance programme in Japan to investigate the safety of tocilizumab for the treatment of rheumatoid arthritis (RA) in the real world. METHODS: This analysis included 3881 patients. Patients received 8 mg/kg of tocilizumab every 4 weeks, and were observed for 28 weeks. Data on baseline characteristics and adverse events (AE) were collected. RESULTS: Total and serious AE were reported as 167 and 27 events/100 patient-years, respectively. The most frequent AE and serious AE were infections. Logistic regression analysis identified the following risk factors for the development of serious infection: concurrent or medical history of respiratory disorders; prednisolone dose at baseline ≥5 mg/day; and age ≥65 years. Twenty-five patients died, and the standardised mortality ratio, with the Japanese general population in 2008 as reference, was 1.66, similar to the results from the Japanese cohort study for RA patients. CONCLUSIONS: Tocilizumab is acceptably safe in the real clinical setting. Tocilizumab needs to be used with consideration of the benefit-risk balance to avoid serious infections in elderly patients and those on high doses of corticosteroids or with a concurrent or medical history of respiratory disorders.

Postmarketing surveillance of safety and effectiveness of etanercept in Japanese patients with rheumatoid arthritis.

Our aim was to evaluate real-world safety and effectiveness in a 6-month postmarketing surveillance study covering all Japanese patients with rheumatoid arthritis (RA) who received etanercept during a 2-year period. Data for 13,894 patients (1334 sites) enrolled between March 2005 and April 2007 were collected. Adverse events (AEs) and serious adverse events (SAEs) were reported in 4336 (31.2%) and 857 (6.2%) patients, respectively. The most frequent AEs were injection site reactions (n = 610, 4.4%) and rash (n = 339, 2.4%), whereas pneumonia (n = 116, 0.8%) and interstitial lung disease (n = 77, 0.6%) were the most frequent SAEs. Significant improvement in the proportion of patients with a good European League Against Rheumatism (EULAR) response was observed from week 4 (17.6%) to week 24 (31.6%) (p < 0.001); 84.3% of patients had good or moderate EULAR responses at week 24. The percentage of patients achieving remission increased significantly from week 4 (9.3%) to week 24 (18.9%) (p < 0.001). Patients with early moderate RA were less likely to experience SAEs and were more likely to achieve remission compared with patients with more severe disease. The safety and effectiveness of etanercept was demonstrated in Japanese patients in one of the largest observational trials conducted thus far in RA patients treated with biologics.

T-box 21 transcription factor is responsible for distorted T(H)2 differentiation in human peripheral CD4+ T cells.

BACKGROUND: Regardless of T(H)1/T(H)2 theory, CD4(+) T cells of patients with allergic asthma, a typical T(H)2 disease, and those of healthy subjects expressed equivalent levels of IFN-gamma, even though T(H)2 cytokines were significantly upregulated in asthmatic patients. OBJECTIVE: The mechanisms underlying distorted T(H)2 cell polarization in human T cells were elucidated. METHODS: Cytokine-producing activity and the expression of T(H)1/T(H)2-specific transcription factors in naïve, T(H)1/T(H)2, or both CD4(+) T cells derived from human peripheral and cord blood were comparatively analyzed. The mechanisms of the differential expression of T-box 21 transcription factor (T-bet) in the cells were assessed by determining the chromatin accessibility at the TBX21 gene. The functional roles of T-bet and other transcription factors in human T(H)1/T(H)2 differentiation were further investigated. RESULTS: T(H)2 cells derived from naive CD4(+) T cells in peripheral blood but not in cord blood produced IFN-gamma. T-bet was expressed in peripheral, but not cord blood, resting naive T cells. Consistently, the accessibility at the proximal TBX21 gene promoter in peripheral naive T cells was higher than that in cord blood naive T cells. IFN-gamma-producing activity was induced in T(H)2-differentiated cord blood T cells by means of ectopic expression of T-bet. In addition, a reduction of T-bet in peripheral T cells suppressed IFN-gamma production. T-bet not only upregulated IFN-gamma but also downregulated IL-4 and IL-13 gene transcription, independently of the modification of T(H)1/T(H)2 balance. CONCLUSION: The expression of T-bet at a naive stage is crucial for the development of IFN-gamma-producing T cells in human peripheral blood, even in T(H)2-related diseases.

Heterogeneous pathogenic processes of thrombotic microangiopathies in patients with connective tissue diseases.

To clarify the pathogenic processes of thrombotic microangiopathies (TMAs) in patients with connective tissue disease (CTD), we analysed clinical characteristics and plasma ADAMTS13 levels in 127 patients with CTD-TMAs, including patients with systemic lupus erythematosus (SLE), systemic sclerosis, polymyositis/dermatomyositis, and rheumatoid arthritis (RA), and 64 patients with acquired idiopathic thrombotic thrombocytopenic purpura (ai-TTP). Plasma levels of ADAMTS13 activity, antigen, and inhibitors were determined by enzyme immunoassays. IgG type anti-ADAMTS13 antibodies were also detected by immunoblots using purified ADAMTS13. ADAMTS13 activity was significantly decreased in CTD-TMAs, regardless of the underlying disease, but the frequency of severe deficiency (defined as <0.5% of normal) was lower in CTD-TMA patients than in ai-TTP patients (16.5% vs. 70.3%, p < 0.01). Severe deficiency of ADAMTS13 activity was predominantly detected in patients with RA- and SLE-TMAs, and was closely associated with the presence of anti-ADAMTS13 IgG antibodies. CTD-TMA patients with severe deficiency of ADAMTS13 activity appeared to have lower platelet counts and better therapeutic outcomes. At least two phenotypic TMAs occur in patients with CTDs: a minor population with deficient ADAMTS13 activity caused by neutralising autoantibodies, and a major population with normal or moderately reduced activity. Classifying CTD-TMAs by ADAMTS13 activity may be useful in predicting the clinical course and therapeutic outcomes, as patients with moderately reduced activity are likely to have more prominent renal impairment and poor prognoses.