Pregnancy outcomes in women with rheumatic diseases: a real-world observational study in Japan.

OBJECTIVES: We aimed to evaluate the obstetric complications and the risk factors for these events in pregnant women with rheumatic diseases (RDs). METHODS: A single-center retrospective study of women with RDs at Hokkaido University Hospital between 2007 and 2016 was conducted. Clinical features and maternal and fetal outcomes were retrospectively collected. The rate of pregnancy complications was compared with the general obstetric population (GOP) in Japan. RESULTS: Overall, 132 pregnancies in 95 women with RDs were recorded. Underlying RDs were systemic erythematosus (SLE) (n = 57), antiphospholipid syndrome (APS) (n = 35), rheumatoid arthritis (n = 9), and other RDs (n = 31). Antiphospholipid antibodies (aPL) were detected in 44 pregnancies (32%). Glucocorticoid was used in 82 pregnancies (62%), and tacrolimus in 20 pregnancies (15%). There were 24 disease flares (18%), but no RD-related death was documented. We recorded 112 live births, 6 abortions, 8 miscarriages, and 6 stillbirths. Pregnancies with RDs appeared to have frequent, emergency cesarean sections and preterm deliveries compared with GOP (30% vs 15% and 21% vs 14%, respectively). The median [interquartile range] birthweight in SLE and APS was lower than GOP (2591 [2231-2958] g and 2600 [2276-2920] g vs 2950 [2650-3250] g, respectively). In pregnancies with SLE, low complement levels presented the risk of maternal complications (odds ratio [95% CI]; 3.9 [1.0-14.9], p = 0.046) and anti-DNA antibody positivity was significantly correlated with the risk of fetal complications (3.5 [1.1-11.2], p = 0.036). In pregnancies with APS, maternal age over 35 years and duration of disease longer than 9 years (7.4 [1.3-40.8], p = 0.021, and 11.16 [1.1-118.8], p = 0.046, respectively) were significantly correlated with the risk of fetal complications. CONCLUSION: Pregnancies with RDs were at increased risk of having both maternal complications and adverse neonatal outcomes, indicating these pregnancies should be closely monitored.

Factor Xa inhibitors for preventing recurrent thrombosis in patients with antiphospholipid syndrome: a longitudinal cohort study.

OBJECTIVE: The objective of this study was to clarify the efficacy and safety of factor Xa inhibitors for antiphospholipid syndrome patients in real world utilization. METHODS: This is a retrospective cohort study comprised of all consecutive patients with antiphospholipid syndrome in our department over a period of 28 years. Patients treated with factor Xa inhibitors were extracted from the cohort. As a control group, patients treated with warfarin were selected from the same cohort with matched age, gender, coexistence of systemic lupus erythematosus, and the presence of antiplatelet therapy, after which we used a propensity score for each of the risk factors as an additional covariate in multivariate Cox proportional hazard regression. The primary endpoint was set as thrombotic and hemorrhagic event-free survival for five years. RESULTS: Among 206 patients with antiphospholipid syndrome, 18 had a history of anti-Xa therapy (five rivaroxaban, 12 edoxaban, one apixaban). Fourteen out of 18 patients on anti-Xa therapy had switched to factor Xa inhibitors from warfarin. Event-free survival was significantly shorter during anti-Xa therapy than that during warfarin therapy (hazard ratio: 12.1, 95% confidence interval: 1.73-248, p = 0.01) ( Figure 1(a) ). Similarly, event-free survival in patients treated with factor Xa inhibitors was significantly shorter compared with controls (hazard ratio: 4.62, 95% confidence interval: 1.54-13.6, p = 0.0075). In the multivariate Cox proportional hazard model, event-free survival in patients with anti-Xa therapy remained significantly shorter (hazard ratio: 11.9, 95% confidence interval: 2.93-56.0, p = 0.0005). CONCLUSIONS: Factor Xa inhibitors may not be recommended for antiphospholipid syndrome.

Effects of statins on thrombosis development in patients with systemic lupus erythematosus and antiphospholipid antibodies.

The objective of this study is to identify the effects of statins and risk factors for thrombosis in patients with new onset of systemic lupus erythematosus (SLE) with or without antiphospholipid antibodies (aPL). Consecutive patients with SLE without history of thrombotic events were retrospectively enrolled from April 1997 to February 2014. The development of first thrombosis and death caused by thrombosis were defined as the study endpoint. Risk and protective factors for developing thrombosis were analyzed. A total of 152 patients, 80 positive and 72 negative for aPL, were included. In aPL-positive patients, 15 developed arterial ( n = 6) and venous ( n = 9) thrombosis (median follow-up period 69 months). Cox's proportional hazards model showed that older age at SLE onset and IgG-anticardiolipin antibodies (aCL) were statistically significant risks for thrombosis. Statin therapy was identified as a statistically significant protective factor against thrombosis (hazard ratio 0.12, 95% confidence interval 0.01-0.98). In aPL-negative patients (median follow-up period 46 months), seven patients developed thrombosis (five arterial and two venous). No risk factors for thrombosis were found in this group. In aPL-positive patients with SLE, the late disease onset and the presence of IgG-aCL represented additional risk factors for thrombosis. Statin treatment appeared as a protective factor for thrombosis.

Thrombotic risk stratification by platelet count in patients with antiphospholipid antibodies: a longitudinal study.

Essentials Thrombotic risk stratification is an unmet need in antiphospholipid antibody carriers. Platelet count and antiphospholipid score (aPL-S) were combined to predict thrombotic events. Patients with high aPL-S are at high thrombotic risk regardless of platelet count. If platelet count is low, patients with low aPL-S are also on high thrombotic risk. SUMMARY: Background Thrombocytopenia is a non-criteria clinical manifestation of antiphospholipid syndrome. However, it remains to be elucidated whether thrombocytopenia increases thrombotic risk in antiphospholipid antibody (aPL) carriers. Objectives To investigate the impact of platelet count in terms of predicting thrombotic events in aPL carriers, and to stratify the thrombotic risk by combining platelet count and antiphospholipid score (aPL-S), which represents a quantification of aPL varieties and titers. Patients/methods A single-center, retrospective, longitudinal study comprising 953 consecutive patients who were suspected of having autoimmune disease between January 2002 and December 2006 was performed. Low platelet count was defined as a count of < 150 × 103 µL-1 at the time of aPL testing. Results A negative correlation was observed between aPL-S and platelet count (r = - 0.2477). Among aPL-positive patients, those with a low platelet count developed thrombosis more frequently than those without (hazard ratio [HR] 2.95, 95% confidence interval [CI] 1.11-7.88). Among aPL-negative patients, no difference was found in the predictive value of thrombosis regardless of platelet count. Patients with aPLs were further divided into two subgroups according to aPL-S. Among low-aPL-S patients, those with low platelet counts developed thrombosis more frequently than those without (HR 3.44, 95% CI 1.05-11.2). In contrast, high-aPL-S patients developed thrombosis frequently regardless of platelet count. Conclusions aPL carriers with low platelet counts are at high risk of developing thrombosis. In particular, 'low-aPL-S carriers' may be stratified by platelet count in terms of predicting future thrombotic events.

Leukemia cutis in an elderly patient treated with low dose cytosine arabinoside and etoposide.

A 78-year-old man presented with a generalized erythematous papular rash. Such skin lesions were not painful, tender or pruritic, and spread over the truncus. He was admitted to our hospital for examination of the skin lesions. Laboratory tests indicated microcytic hypochromatic anemia and thrombocytopenia, although gave a normal leukocyte count with normal differentiation. His bone marrow showed hypercellularity, with 43% peroxidase positive blasts that displayed positive immunophenotypes for CD4, CD13, CD33, CD41a, KP-1 (CD68), and HLA-DR. His skin specimen revealed infiltration in the dermis and subcutaneous fat tissue by leukemic cells that were positive for the leukocyte common antigen (LCA, CD45), CD15, CD33, CD68, and HLA-DR. He was diagnosed as having M4 subtype of acute myelogeneous leukemia (AML) with leukemia cutis. After three courses of low dose cytosine arabinoside (LDAC), combined with low dose etoposide, he achieved complete remission (CR). He remained well, with no evidence of relapse nine months later. LDAC should be considered as initial treatment for such cases of leukemia cutis with poor general condition.

[Antihypertensive substance in the leaves of kumis kucing (Orthosiphon aristatus) in Java Island].

The water decoction of leaves of kumis kucing, Orthosiphon aristatus (BL.) MIQ (Lamiaceae) which has been prescribed in Javanese traditional medicine (jamu) for the treatment of hypertension etc., was partitioned into a mixture of chloroform and water. The chloroform-soluble portion showed an inhibitory effect on the contractile responses on rat thoracic aorta smooth muscle stimulated with KCl beforehand, while the water-soluble portion showed no effect. The chloroform-soluble portion was separated to afford a new benzochromene [orthochromene A (7)], two new isopimarane-type diterpenes [orthosiphonone A (10), orthosiphonone B (11)], and two novel migrated pimarane-type diterpenes [neoorthosiphol A (12), neoorthosiphol B (13)], together with eight known compounds (1-6, 8, 9). Among those thirteen substances, it was found that a major constituent in the water decoction of leaves, methylripariochromene A (5), exhibited a continuous decrease in systolic blood pressure after subcutaneous administration in conscious stroke-prone spontaneously hypertensive rats (SHRSP).

[Perforation of small intestinal during hematologic recovery in an elderly man after induction therapy for acute lymphoblastic leukemia L3].

A 67-year-old man with a 7-month history of dilated cardiomyopathy was admitted to our hospital because of general fatigue, shortness of breath, and anemia on laboratory examination. Increased blasts were observed in the bone marrow. The blasts were characterized by large cells with abundant, intensely basophilic, vacuolated cytoplasm, round nuclei, and prominent nucleoli. Chromosome analysis revealed a nonrandom t(8;22)(q24;q11) chromosomal abnormality, and surface-marker analysis disclosed a positive immunophenotype for CD10, CD19, CD20, CD38, HLA-DR, FMC7, and IgM-lambda. These findings yielded a diagnosis of L3 acute lymphoblastic leukemia. The patient was treated with chemotherapeutic agents. On the 39th hospital day, during hematologic recovery after induction therapy, abdominal pain developed. Abdominal X-ray films disclosed ileus with dilatation of the small bowel and Kerckring's folds. Conservative treatment was begun but the patient died. At autopsy, intestinal perforations were observed at a site 55 cm proximal to the ileocecal junction. A specimen of perforated tissue revealed a diffuse infiltration of leukemic cells through the small bowel wall. However, bone marrow specimens showed no signs of aggravation of leukemia.

[Acute lymphoblastic leukemia with breast infiltration during the second trimester of pregnancy and followed by successful delivery].

A 27-year-old pregnant woman was admitted to a local hospital because of headache, nausea, and general fatigue. Her blood examination showed leukocytosis, anemia, and thrombocytopenia. She was referred to our hospital in March 1998. Her bone marrow was normocellular with an excess of blasts (89.1%, peroxidase stain(-), PAS stain(-)) that displayed a positive immunophenotype for CD2, CD4, CD5, CD7, CD34, CD38, and CD71. Chromosome analysis revealed complex abnormal karyotypes. The patient was given a diagnosis of acute lymphoblastic leukemia associated with central nervous system and breast infiltration, and received induction chemotherapy during the second trimester of her pregnancy. After she achieved complete remission, a cesarean section was performed, and a healthy baby delivered. Our experience in this case demonstrated that combination chemotherapy during the second trimester of pregnancy is feasible.

[CD30-positive anaplastic large cell lymphoma of bone treated with autologous peripheral blood stem cell transplantation].

A 30-year-old man was admitted to our hospital with the chief complaints of fever and pain in the right shoulder, axilla, and inguinocrural region. Computed tomography, magnetic resonance imaging, 67Ga-scintigraphy, and bone-scintigraphy revealed osteolytic lesions in the ribs and right ilium. Biopsy specimens from lesions in the right ilium confirmed the diagnosis of CD 30-positive anaplastic large cell lymphoma. The patient was treated with 6 courses of CHOP therapy followed by high-dose chemotherapy and autologous peripheral blood stem cell transplantation. He achieved and remained in remission with no evidence of relapse 14 months later.

The E3 ligase PIRH2 polyubiquitylates CHK2 and regulates its turnover.

The serine threonine kinase checkpoint kinase 2 (CHK2) is a DNA damage checkpoint protein important for the ATM-p53 signaling pathway. In addition to its phosphorylation, CHK2 is also ubiquitylated, and both post-translational modifications are important for its function. However, although the mechanisms that regulate CHK2 phosphorylation are well established, those that control its ubiquitylation are not fully understood. In this study, we demonstrate that the ubiquitin E3 ligase PIRH2 (p53-induced protein with a RING (Really Interesting New Gene)-H2 domain) interacts with CHK2 and mediates its polyubiquitylation and proteasomal degradation. We show that the deubiquitylating enzyme USP28 forms a complex with PIRH2 and CHK2 and antagonizes PIRH2-mediated polyubiquitylation and proteasomal degradation of CHK2. We also provide evidence that CHK2 ubiquitylation by PIRH2 is dependent on its phosphorylation status. Cells deficient in Pirh2 displayed accumulation of Chk2 and enhanced hyperactivation of G1/S and G2/M cell-cycle checkpoints. This hyperactivation was, however, no longer observed in Pirh2-/-Chk2-/- cells, providing evidence for the importance of Chk2 regulation by Pirh2. These findings indicate that PIRH2 has central roles in the ubiquitylation of Chk2 and its turnover and in the regulation of its function.

Up regulated expression of tumour necrosis factor {alpha} converting enzyme in peripheral monocytes of patients with early systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is accompanied by abnormalities in humoral and cellular immune systems. OBJECTIVE: To determine the genes specifically expressed in the immune system in SSc by analysis of the gene expression profile of peripheral blood mononuclear cells (PBMC) from patients with SSc, including those treated with haematopoietic stem cell transplantation (HSCT). Additionally, to investigate the clinical significance of the up regulation of tumour necrosis factor alpha (TNFalpha) converting enzyme (TACE). METHODS: PBMC from patients with SSc (n = 23) and other autoimmune diseases (systemic lupus erythematosus (SLE, n = 16), rheumatoid arthritis (RA, n = 29)), and from disease-free controls (n = 36) were examined. Complementary DNA arrays were used to evaluate gene expression of PBMC, in combination with real time quantitative polymerase chain reactions. TACE protein expression in PBMC was examined by fluorescence activated cell sorter (FACS). RESULTS: In patients with SSc 118 genes were down regulated after HSCT. Subsequent comparative analysis of SSc without HSCT and healthy controls indicated SSc-specific up regulation for three genes: monocyte chemoattractant protein-3 (p = 0.0015), macrophage inflammatory protein 3alpha (p = 0.0339), and TACE (p = 0.0251). In the FACS analysis, TACE protein was mainly expressed on CD14(+) monocytes both in patients with SSc and controls. TACE expression on CD14(+) cells was significantly increased in patients with early SSc (p = 0.0096), but not in those with chronic SSc, SLE, or RA. TACE protein levels in SSc monocytes correlated with the intracellular CD68 levels (p = 0.0016). CONCLUSIONS: Up regulation of TACE expression was a unique profile in early SSc, and may affect the function of TNFalpha and other immunoregulatory molecules.

[Two cases of classical polyarteritis nodosa associated with a low titre of MPO-ANCA].

We studied two autopsy cases, each with a low titre of myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) associated with systemic vasculitis. It was difficult to distinguish these cases from classic polyarteritis nodosa. The patients had suffered from continuous fever, malaise, and weight loss: however, their renal insufficiency was clinically mild over the course of their disease. The patients were diagnosed initially as having MPO-ANCA-associated vasculitis and were treated with prednisolone. Their clinical status improved, but unfortunately, they died of an infectious disease. Autopsies revealed systemic vasculitis in small arteries with no signs of necrotizing and crescentic glomerulonephritis. Our pathologist subsequently diagnosed both cases as classic polyarteritis nodosa. Systemic vasculitis associated with MPO-ANCA is usually considered to be a microscopic polyarteritis. However, classic polyarteritis nodosa should always be considered as a possibility for those patients with mild renal insufficiency and a low titre of MPO-ANCA.

Indonesian medicinal plants. XXIII. Chemical structures of two new migrated pimarane-type diterpenes, neoorthosiphols A and B, and suppressive effects on rat thoracic aorta of chemical constituents isolated from the leaves of Orthosiphon aristatus (Lamiaceae).

Two novel migrated pimarane-type diterpenes named neoorthosiphols A (1) and B (2) were isolated from the water decoction of the leaves of Orthosiphon aristatus (Lamiaceae), which has been prescribed in Javanese traditional medicine (jamu) for the treatment of hypertension, etc. The absolute chemical structures have been elucidated on the basis of physicochemical properties. It has been found that two migrated pimarane-type diterpenes (1, 2), four isopimarane-type diterpenes (3, 4, 5, 6), three benzochromenes (7, 8, 9) and two flavones (12, 13) exhibit a suppressive effect on contractile responses in rat thoracic aorta, among thirteen chemical constituents (1-13) isolated from the leaves.

Thrombotic thrombocytopenic purpura in a patient with rapidly progressive scleroderma.

Abstract A 57-year-old man presented with palpitations, shortage of breath on exertion, and rapidly progressive scleroderma. On admission, a computed tomographic scan of his lung showed active interstitial pneumonia. We treated him with d-penicillamine and intravenous pulse methylprednisolone. After this treatment, severe abdominal pain, microangiopathic hemolytic anemia, thrombocytopenia, and progressive renal involvement appeared. We diagnosed him as having systemic sclerosis (SSc) complicated by thrombotic thrombocytopenic purpura. At postmortem, thromboses of capillaries, arterioles, and small arteries were found in several organs. As well as the differential diagnosis of SSc with thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and renal involvement, we diagnosed scleroderma renal crisis (SRC), normotensive renal crisis (NRC), and SSc complicated by TTP. Typical SRC and NRC were excluded because his blood pressure was in the normal range without elevation of plasma renin activity or azotemia over his clinical course. Although distinguishing TTP from renal crisis is difficult, an evaluation of ultra-large multimers of von Willebrand factor (UL-vWF) concentration may be helpful in these situations.

Splenomegaly and chronic disseminated intravascular coagulation in Osler-Weber-Rendu disease: a case report.

A 45-year-old Japanese woman with splenomegaly and thrombocytopenia was referred to our hospital. The diagnosis of Osler-Weber-Rendu disease (Osler's disease) was made because of spotty telangiectasia on her tongue, recurrent epistaxis since childhood, and a diathesis indicated by her family history. The patient's laboratory examination revealed anemia, thrombocytopenia, and other data consistent with chronic disseminated intravascular coagulation (DIC). Bone marrow examination was normal. Abdominal computed tomography showed marked enlargement of the spleen with deformity and calcified plaque, not homogeneously enhancing. Hypersplenism was not observed. Platelet scintigraphy indicated a remarkable uptake in the spleen. She was diagnosed as having chronic DIC associated with vascular lesions of Osler's disease in the spleen. Splenectomy was performed and the subsequent pathological findings indicated that fragility of the fine vascular architecture of the splenic red pulp might have been responsible for pathogenesis. The large pooling of blood with coagulation was thought to be secondary.

Changes in the T-helper cell 1/T-helper cell 2 balance of peripheral T-helper cells after autologous peripheral blood stem cell transplantation for non-Hodgkin's lymphoma.

The purpose of this study was to analyze changes in the T-helper cell 1/T-helper cell 2 (Th1/Th2) balance of peripheral T-helper cells after autologous peripheral blood stem cell transplantation (auto-PBSCT) for non-Hodgkin's lymphoma (NHL) and to evaluate the effects of chemotherapy and granulocyte colony-stimulating factor (G-CSF) on the Th1/Th2 balance. A series of peripheral blood samples from four patients with NHL were collected before peripheral blood stem cell harvest and after auto-PBSCT. Using flow cytometry, Th1 and Th2 cells were identified by their intracellular cytokines: interleukin (IL)-4-/interferon (IFN)-gamma+ and IL-4+/IFN-gamma-, respectively. The Th1/Th2 balance was estimated as the ratio of IL4-/IFN-gamma+ cells to IL-4+/IFN-gamma- cells. Although the Th1/Th2 balance decreased initially, it increased markedly 28 days after the cessation of G-CSF, following auto-PBSCT, in parallel with an increase in lymphocytes. This increase was mainly due to an increase in the proportion of Th1 cells. The Th1/Th2 balance did not change appreciably before PBSC harvest. Serum IFN-gamma increased after auto-PBSCT in three patients. These preliminary data demonstrate that, after auto-PBSCT for NHL, the Th1/Th2 balance decreases initially and then increases after 1 month to levels above pretreatment levels and that the effects of chemotherapy and G-CSF on the Th1/Th2 balance are negligible before PBSC harvest. Further evaluation of the Th1/Th2 balance after allogeneic PBSCT at the single-cell level should be undertaken using this method.

Transient myopia with severe chemosis as an initial manifestation of systemic lupus erythematosus.

Abstract A 24-year-old woman suffered from blurred vision and periorbital edema with remittent fever. She was diagnosed as having systemic lupus erythematosus (SLE), complicated with myopia and retinopathy and severe chemosis. Antiphospholipid syndrome (APS), hemophagocytic syndrome, and liver involvement were also proven. We considered that APS might cause chemosis as a result of thrombosis-induced perfusion failure in the conjunctiva. In such cases, APS should be considered and anticoagulation therapy associated with steroid therapy should be initiated. In systemic lupus erythematosus (SLE), chemosis, severe hepatitis, and hemophagocytic syndrome (HPS) are rare complications. It is well known that many cases of SLE are complicated with antiphospholipid syndrome (APS), which causes arteriovenous thrombosis. We report a case of SLE with transient myopia and severe chemosis complicated with severe hepatitis and HPS. As this patient had antiphospholipid antibodies, these ocular complications were considered to be related to APS.

Liver dysfunction due to apoptosis in a patient with systemic lupus erythematosus.

We report on a 23-year-old Japanese female with a 13-year history of systemic lupus erythematosus (SLE), and two episodes of deterioration followed by treatment with high dose prednisolone. Although she had been recently treated with prednisolone (12.5 mg daily), her liver function became worse in July 1998. Results of a liver biopsy revealed multi-focal hepatic cell death in a severe fatty liver, without any inflammatory cell invasion. The biopsy also showed a positive TUNEL (Tdt-catalysed DNA nick end labelling) reaction indicating apoptosis. Her liver function recovered rapidly following steroid pulse therapy. Serum soluble Fas ligand (sFasL) was found to be elevated to a concentration of 0.395 ng/ml at the time of liver damage, but was less than 0.03 ng/ml before liver damage and after prednisolone treatment. The liver damage in this case appeared to be involved with apoptosis induced by sFasL. Although hepatitis associated with SLE is rare, apoptosis directly related to elevated sFasL levels might cause this complication.