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The objective of this study is to describe a series of patients above the age of 50 years with large vessel arteritis and vascular involvement typical of TAK. A retrospective review of 18 patients (median age 64 years) with emphasis on clinical characteristics, laboratory values, and vascular involvement by CT, MRI, or planar angiography. Five patients fulfilled the ACR criteria for GCA, five for TAK, three both GCA and TAK, while five patients did not fulfill the criteria for either disease. The dominant presenting symptoms were constitutional, while only a few patients had cranial or peripheral symptoms. Sixty-one percent had physical signs of vascular compromise. Temporal artery biopsy showed giant cell arteritis in six out of nine biopsies. Arterial involvement: 78 % had either involvement of the ascending aorta, the aortic arch, descending or/and abdominal aorta, 9 carotid, 12 subclavian, 5 axillary, 3 renal, 7 iliac, and 2 femoral arteries; 7 mesenteric or celiac trunk. All the patients were treated with prednisone and 50 % with steroid-sparing drug. Nine out of 15 patients (60 %) achieved remission after 1 year of follow-up. No substantial differences in the distribution of vascular involvement, type of treatment, or outcome measures were observed between patients fulfilling criteria for GCA or TAK. Vascular involvement typical of TAK in patients above the age of 50 years with large vessel arteritis seems to be more frequent than previously assumed. Our findings support the assumption that TAK and GCA represent a spectrum of the same disease.

Objective Low dose (10–25 mg/week) methotrexate is widely used for the management of systemic inflammatory diseases, and is considered to be relatively safe. Toxicity due to low dose MTX has been reported but is poorly characterized. We describe the clinical features, risk factors, and outcomes of low dose MTX toxicity in a large case series at our center. Patients and methods We conducted a retrospective case series of all adult (> 18 years) patients hospitalized at Sheba Medical Center, between 2005 and 2012 for low dose MTX toxicity. Results We identified 28 patients (age: 70.4 ± 13.7 years, range: 33–88; 20 (71%) females) hospitalized for low dose MTX toxicity. Indications for MTX therapy included: rheumatoid arthritis (39.2%), psoriasis ± arthritis (21.5%), polymyalgia rheumatica (10.8%) and other inflammatory conditions (28.5%). Pancytopenia was the most common manifestation of low dose MTX toxicity detected in 78.5% of the patients. Potential risk factors included acute renal failure, hypoalbuminemia, concurrent use of drugs known to interact with MTX, and dose errors. Serum MTX concentrations (n = 20, mean 0.04 ± 0.07 μg/mL range: 0–0.3) did not correlate with the degree of either neutropenia (r = − 0.36; p = 0.18) or thrombocytopenia (r = 0.44; p = 0.10). Seven (25%) patients died, all from pancytopenia followed by sepsis. Serum MTX concentrations did not differ between the patients who died from MTX toxicity (n = 6; mean: 0.05 ± 0.04 μg/mL) and those who survived the toxicity (n = 14 mean 0.04 ± 0.08; p = 0.45). Conclusions Low-dose MTX toxicity can be life threatening, mainly due to myelosuppression. There is no rationale for MTX therapeutic drug monitoring in the setting of low-dose toxicity.

Introduction MRI and MRA are used for diagnosis and activity determination of patients with Takayasu's arteritis (TA). However, there is a limited experience regarding the role of MRI in long-term follow-up of those patients. The aim of the present study was to evaluate the clinical usefulness of MRI in the long-term follow-up of patients with Takayasu's disease. Materials and methods The clinical data of 11 TA patients, who obtained two or more follow-up MRI scans, was matched with the imaging results. MRI examinations were considered positive for disease activity when one of the following findings was noted: new arterial wall enhancement or interval appearance of anatomical changes (interval dilatation, stenosis or occlusion or new arterial wall irregularity). Conversely, MRI examinations were considered to show signs of improvement when local enhancement disappeared, or when a stenosis was relieved. Disease activity was determined by the combination of worsening localizing ischemic signs and symptoms, systemic signs and symptoms (malaise, fever, etc.), and elevated blood markers (CRP and ESR). Results A total of 47 MRI examinations were performed in 11 patients (1 male, mean age 28, range 14–53 years) with a total follow-up time ranging between 12 and 56 months (average 36 months). MRI was positive for active disease at least once in nine out of the 11 patients (82%). The most commonly affected arteries were the aortic arch, the left subclavian artery and the left common carotid artery. No statistically significant correlation was found between clinical activity and MRI signs of activity. Conclusion Although MRI is a well established modality for primary diagnosis of TA, the present study suggests that it has a limited clinical role in the long-term follow-up of those patients when reactivation of disease is suspected.

Objective. To investigate whether in patients with antiphospholipid syndrome (APS), high positive antibody titers are associated with adverse pregnancy outcome. Design. A retrospective cohort study of prospectively collected data. Setting. Sheba Medical Center, Israel, a tertiary referral center. Population sample. Pregnant women with APS. Methods. Anticardiolipin, a-β2-glycoprotein I antibodies, and lupus anticoagulant were measured before pregnancy. Women were divided into those with antibody titers >four times the upper limit of normal (high positive titer, HPT group), and the rest, into the positive titer (PT) group. All women were treated with daily enoxaparin and aspirin. Main outcome measures. Composite adverse fetal/neonatal outcome, defined as one or more of the following: fetal/neonatal loss, preterm birth ≤32 weeks, and birthweight below than 10th percentile. Composite adverse fetal/neonatal outcome was compared between the HPT and PT groups. Maternal adverse outcomes were also compared. Results. 51 women with APS were followed during 55 pregnancies, 20 in the HPT and 35 in the PT groups. The two groups were similar with regard to previous obstetric and clinical characteristics. Among HPT women, only 7/20 (35%) pregnancies culminated in appropriately grown, live-born infants >32 weeks’ gestation, compared with 27/35 (77%) PT pregnancies. The risk of adverse fetal/neonatal outcome was 5.7 times higher (95%CI 1.9–17.7) for HPT than for PT women. Conclusions. Pregnant women with APS and high positive antiphospholipid antibody titers are a unique and extremely high risk group for adverse fetal/neonatal outcome. Stricter surveillance and possibly additional therapy options should be explored for this patient population.

Patients with systemic lupus erythematosus (SLE) produce antibodies to many different self-antigens. Here, we investigated antibodies in SLE sera using an antigen microarray containing many hundreds of antigens, mostly self-antigens. The aim was to detect sets of antibody reactivities characteristic of SLE patients in each of various clinical states – SLE patients with acute lupus nephritis, SLE patients in renal remission, and SLE patients who had never had renal involvement. The analysis produced two novel findings: (i) an SLE antibody profile persists independently of disease activity and despite long-term clinical remission, and (ii) this SLE antibody profile includes increases in four specific immunoglobulin G (IgG) reactivities to double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), Epstein–Barr virus (EBV) and hyaluronic acid; the profile also includes decreases in specific IgM reactivities to myeloperoxidase (MPO), CD99, collagen III, insulin-like growth factor binding protein 1 (IGFBP1) and cardiolipin. The reactivities together showed high sensitivity (> 93%) and high specificity for SLE (> 88%). A healthy control subject who had the SLE antibody profile was later found to develop clinical SLE. The present study did not detect antibody reactivities that differentiated among the various subgroups of SLE subjects with statistical significance. Thus, SLE is characterized by an enduring antibody profile irrespective of clinical state. The association of SLE with decreased IgM natural autoantibodies suggests that these autoantibodies might enhance resistance to SLE.

Patients having systemic rheumatic diseases constitute a small percentage of admissions to the medical intensive care units (ICUs). Dermatomyositis (DM) is one of the rheumatic diseases that have secondary complications that may lead to a critical illness requiring hospitalization in the ICU. Herein, we present the features, clinical course, and outcome of critically ill patients having DM who were admitted to the ICU. The medical records of six DM patients admitted to the ICU in a large tertiary hospital in a 12-year period were reviewed. The mean age of patients at time of admission to the ICU was 38 (range 16-37). Mean disease duration from diagnosis to admission to the ICU was 1.6 years (range 1 month-8 years), while the main reason for admission to the ICU was acute respiratory failure. Two of six patients died during the hospitalization. The main causes of death were respiratory complications and sepsis. The outcome of DM patients admitted to the ICU was generally not different from the outcome of other patients hospitalized in the ICU. The main reason for hospitalization was acute respiratory failure. As there are many reasons for respiratory failure in DM, an early diagnosis and aggressive appropriate treatment may help to further reduce the mortality in these patients.

The objective of this study was to assess the safety of induction of ovulation and oocyte retrieval in patients at risk of thrombosis, necessitating treatment with anticoagulants. Twenty-four patients considered as high risk for a thromboembolic event underwent 73 IVF cycles and 68 oocyte retrieval procedures, and were treated concomitantly with anticoagulation therapy (low molecular weight heparin; LMWH). A subgroup of five patients considered at especially high risk for thrombosis was isolated. These patients were prepared for oocyte retrieval using a controlled spontaneous cycle. All these patients were programmed exclusively for surrogacy. Nineteen women underwent 49 cycles of ovulation induction with gonadotrophins. The average peak oestradiol concentration was 1791 +/- 1420 pg/ml with an average of 13.5 +/- 8.4 oocytes retrieved in each cycle. The five patients from the very high risk group underwent 24 cycles: the average peak oestradiol concentration was 163 +/- 98 pg/ml. In 18, an egg was retrieved and in 14, fertilization was achieved. No bleeding or thromboembolic complications were noted during treatment of both groups of patients. It is concluded that during induction of ovulation in patients at risk for thrombosis, the introduction of LMWH as a cycle protective treatment was not associated with any medical complication. The use of a controlled spontaneous cycle with LMWH is suggested in very high risk patients.

Systemic lupus erythematosus (SLE) is an autoimmune disease that can attack many different body organs; the triggering event is unknown. SLE has been associated with more than 100 different autoantibody reactivities - anti-dsDNA is prominent. Nevertheless, autoantibodies to dsDNA occur in only two-thirds of SLE patients. We previously reported the use of an antigen microarray to characterize SLE serology. We now report the results of an expanded study of serology in SLE patients and scleroderma (SSc) patients compared with healthy controls. The analysis validated and extended previous findings: two-thirds of SLE patients reacted to a large spectrum of self-molecules that overlapped with their reactivity to dsDNA; moreover, some SLE patients manifested a deficiency of natural IgM autoantibodies. Most significant was the finding that many SLE patients who were negative for autoantibodies to dsDNA manifested abnormal antibody responses to Epstein-Barr virus (EBV): these subjects made IgG antibodies to EBV antigens to which healthy subjects did not respond or they failed to make antibodies to EBV antigens to which healthy subjects did respond. This observation suggests that SLE may be associated with a defective immune response to EBV. The SSc patients shared many of these serological abnormalities with SLE patients, but differed from them in increased IgG autoantibodies to topoisomerase and centromere B; 84% of SLE patients and 58% of SSc patients could be detected by their abnormal antibodies to EBV. Hence an aberrant immune response to a ubiquitous viral infection such as EBV might set the stage for an autoimmune disease.

Objective: Ischemic stroke is the most common neurological manifestation inpatients with antiphospholipid syndrome (APS). Pregnancy in APS patients markedly increases the risk of thrombosis. There is no data on pregnancy outcome in patients with APS with a history of an ischemic stroke. We report our experience with three APS patients with a history of stroke who had successful pregnancies and deliveries. Patients: Three patients with APS and previous stroke were treated with smalldoses of aspirin and anticoagulants during pregnancy. Results: The patients remained free of attacks of cerebral ischemia during their pregnancies and at follow-up periods of 1 to 4 years. Conclusions: Successful pregnancy and delivery is possible in APS patients with a history of stroke, treated with low-dose aspirin and anticoagulants. A previous episode of cerebral ischemia should not be considered an absolute contraindication for an APS patient to become pregnant.

Objective: To describe experience with 41 pregnancies treated with the low-molecular-weight heparin enoxaparin. Methods: The medical charts of 34 women (a total of 41 pregnancies) treated between January 1992 and March 1995 with the low-molecular-weight heparin enoxaparin were reviewed. Most patients (87.5%) received one daily 40-mg injection. In all cases, treatment was continued throughout labor, delivery, and the immediate postpartum period. Results: Therapy was administered for 5–280 days (median 91). One case of a thromboembolic event was recorded during treatment. No systemic or local side effects were reported. During pregnancy, only one patient had mild vaginal bleeding, which resolved spontaneously while therapy was continued. There was no excessive intrapartum bleeding in any of these patients, whether delivered vaginally or abdominally. During treatment, 19 of the 34 patients underwent 24 surgical procedures, including 13 cesarean deliveries, without excessive bleeding. Epidural anesthesia was used during labor in nine of the patients, with no specific complications. The corrected perinatal mortality rate, (ie, the rate of fetal death after 24 weeks' gestation plus neonatal death, excluding a neonate with multiple anomalies) for those neonates delivered after 24 weeks' gestation was 2.7%. There were no cases of intraventricular hemorrhage in any of the neonates. Conclusion: This preliminary series, the largest reported to date, demonstrates the relative safety and efficacy of low-molecular-weight heparin therapy in pregnancy and delivery.

To investigate whether in patients with antiphospholipid syndrome (APS), high positive antibody titers are associated with adverse pregnancy outcome.A retrospective cohort study of prospectively collected data.Sheba Medical Center, Israel, a tertiary referral center. POPULATION SAMPLE: Pregnant women with APS.Anticardiolipin, a-β2-glycoprotein I antibodies, and lupus anticoagulant were measured before pregnancy. Women were divided into those with antibody titersfour times the upper limit of normal (high positive titer, HPT group), and the rest, into the positive titer (PT) group. All women were treated with daily enoxaparin and aspirin.Composite adverse fetal/neonatal outcome, defined as one or more of the following: fetal/neonatal loss, preterm birth ≤ 32 weeks, and birthweight below than 10th percentile. Composite adverse fetal/neonatal outcome was compared between the HPT and PT groups. Maternal adverse outcomes were also compared.51 women with APS were followed during 55 pregnancies, 20 in the HPT and 35 in the PT groups. The two groups were similar with regard to previous obstetric and clinical characteristics. Among HPT women, only 7/20 (35%) pregnancies culminated in appropriately grown, live-born infants32 weeks' gestation, compared with 27/35 (77%) PT pregnancies. The risk of adverse fetal/neonatal outcome was 5.7 times higher (95%CI 1.9-17.7) for HPT than for PT women.Pregnant women with APS and high positive antiphospholipid antibody titers are a unique and extremely high risk group for adverse fetal/neonatal outcome. Stricter surveillance and possibly additional therapy options should be explored for this patient population.

The clinical-pathological conference portrayed in this article took place at the Sheba Medical Center, Tel Hashomer, IsraeL. A 63 year old woman was hospitalized due to a gradually increasing dyspnea. The discussion entailed the differential diagnosis based on the complex past medical history of this patient, the history of the present illness, the Laboratory results and the imaging studies. Thereupon, the aim was to attempt to point out the most probable clinical diagnosis. This article concludes with the pathological discussion and the final anatomical diagnosis. .

Patients with systemic lupus erythematosus (SLE) produce antibodies to many different self-antigens. Here, we investigated antibodies in SLE sera using an antigen microarray containing many hundreds of antigens, mostly self-antigens. The aim was to detect sets of antibody reactivities characteristic of SLE patients in each of various clinical states – SLE patients with acute lupus nephritis, SLE patients in renal remission, and SLE patients who had never had renal involvement. The analysis produced two novel findings: (i) an SLE antibody profile persists independently of disease activity and despite long-term clinical remission, and (ii) this SLE antibody profile includes increases in four specific immunoglobulin G (IgG) reactivities to double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), Epstein–Barr virus (EBV) and hyaluronic acid; the profile also includes decreases in specific IgM reactivities to myeloperoxidase (MPO), CD99, collagen III, insulin-like growth factor binding protein 1 (IGFBP1) and cardiolipin. The reactivities together showed high sensitivity (> 93%) and high specificity for SLE (> 88%). A healthy control subject who had the SLE antibody profile was later found to develop clinical SLE. The present study did not detect antibody reactivities that differentiated among the various subgroups of SLE subjects with statistical significance. Thus, SLE is characterized by an enduring antibody profile irrespective of clinical state. The association of SLE with decreased IgM natural autoantibodies suggests that these autoantibodies might enhance resistance to SLE.

Cardiac conduction defects have not been previously described in association with hyponatremia, although in patients with congestive heart failure the frequency of ventricular premature beats was found to correlate to the severity of hyponatremia. We describe three patients with second-degree or complete atrioventricular (AV) block which occurred during or shortly after an episode of severe hyponatremia. The first had thiazide-induced hyponatremia while on amiodarone. In the second, definite etiology for hyponatremia which was associated with longstanding polydipsia could not be established. The third had ischemic heart disease and intermittent conversion of his first-degree to second-degree AV block while hyponatremic after diuretics use. Although it is usually difficult to single out hyponatremia as the cause of conduction defects which usually occur in the presence of cardiac disease, potent medications or other electrolyte abnormalities, we suggest that hyponatremia may play a role in the pathogenesis of conduction defects in the diseased heart.

Objective To assess platelet function under defined flow conditions in patients with antiphospholipid syndrome (APS) and to correlate the results with thrombotic complications and the presence of subsets of antiphospholipid antibodies (aPL), lupus anticoagulant (LAC), and/or anticardiolipin antibodies (aCL). Methods We studied 88 randomized APS patients with or without a history of thrombosis. Seventeen patients with other thrombosis (no APS) and 26 healthy subjects served as controls. Platelet adhesion and aggregation on the extracellular matrix were measured with a cone-and-plate(let) analyzer (CPA) by examining the percentage of total area covered with platelets (surface coverage [SC]) and the mean size of surface-bound objects (average size [AS]) and were compared with platelet responses to different ADP concentrations by conventional aggregometry. Results Under defined flow conditions, SC and AS were significantly higher for venous thrombosis and arterial thrombosis in APS patients compared with no thrombosis, other thrombosis, and healthy control groups. The increased platelet adhesion and aggregation in APS patients with thrombotic events was associated with higher levels of von Willebrand factor (vWF) antigen (mean ± SD 230.6 ± 51.2%) and ristocetin cofactor activity (181.0 ± 36.0%). No change in CPA and vWF parameters was found in APS patients with positive results for aPL who did not undergo thrombotic events or in patients with other thrombosis. The CPA parameters were neither associated with the high response of platelets to ADP nor associated with the presence of LAC, aCL, or both. The CPA parameters were similarly increased irrespective of aspirin use. The results suggest that the increased adhesion properties of platelets in APS patients could be mediated by high levels and activity of vWF. This complements the known ability of APS antibodies to enhance platelet response to agonists in conventional aggregometry. Conclusion The CPA test was found to be valuable in differentiating APS patients with and without thrombotic complications.

Objective Secondary hypertension during pregnancy usually carries high maternal and fetal morbidity and mortality rates. A rare form of monogenic hypertension is familial hyperkalemia and hypertension, which is caused by mutations in the kinases WNK1 or WNK4 and other unknown molecular defects. The purpose of the study was to examine the course of pregnancy in hypertensive women with familial hyperkalemia and hypertension. Study design We prospectively studied 2 pregnancies of a woman with familial hyperkalemia and hypertension and the Q565E WNK4 mutation (pregnancies 1 and 2) and retrospectively studied the course of 2 pregnancies in another woman who was an affected member of this largest family described in the literature. Results Both women had hypertension (170-190/105-110 mm Hg), hyperkalemia (5.3-6.0 mmol/L), and hypercalciuria, all of which were well controlled by thiazides. During pregnancies, thiazides were discontinued; throughout the pregnancy, the blood pressure remained normal at 120 to 130/75 to 85 mm Hg; however, hyperkalemia and hypercalciuria, which were documented in pregnancies 1 and 2, persisted. Renin and aldosterone levels (which were measured in pregnancies 1 and 2) rose towards their end. Four normal infants were born. A woman with familial hyperkalemia and hypertension of unknown molecular defect who had 2 pregnancies with hypertension exacerbation and premature deliveries was described previously. Conclusion In familial hyperkalemia and hypertension with the WNK4 mutation, pregnancy ameliorates hypertension; however, hyperkalemia and hypercalciuria persist. This dissociation may shed light on the pathogenesis of familial hyperkalemia and hypertension, on pregnancy-related hypertension, and on the mechanism of action of WNK4 kinase, a major regulator of cellular ion transport.

Familial hyperkalemia and hypertension (FHH; pseudohypoaldosteronism type II) is an autosomal dominant disorder characterized by hyperkalemia, hypertension, and low renin. WNK1 kinase overexpression and WNK4 kinase inactivating missense mutations cause FHH. When expressed in frog oocyte, WNK4 inhibits Na-Cl cotransporter surface expression, and WNK1 relieves this inhibition. We have reported hypercalciuria in subjects with the WNK4 Q565E mutation. In contrast, in subjects with WNK1 overexpression, normocalciuria was found. Here we report a major extension of our previously described kindred that contains 34 subjects, 18 of them affected by the mutation. Hypertension was diagnosed in 13 affected subjects at the age of 31 12 yr. Five of the affected or obligatory affected subjects had stroke, in four at the age of 50–62 yr. Seven subjects with FHH were diagnosed 27 yr previously. All four subjects who were normotensive at diagnosis became hypertensive during followup. The mean time between detection of hyperkalemia and appearance of hypertension was 13 yr. In the extended kindred, compared with the unaffected subjects, affected subjects had hyperkalemia, low transtubular potassium gradient, hyperchloremia, low bicarbonate, higher aldosterone, and marked suppression of renin. Urinary calcium levels in affected and unaffected subjects were 0.85 0.27 and 0.28 0.12 mmol/mmol creatinine, respectively (P < 0.0001). Hypercalciuria was accompanied by lower serum calcium levels [9.44 0.15 vs. 9.81 0.31 mg/dl (2.36 0.04 vs. 2.45 0.08 mmol/liter); P 0.01], supporting a mechanism of renal calcium leak. The six affected, currently normotensive subjects had the same degree of hyperkalemia, hypercalciuria, and low renin as the affected hypertensive subjects. We conclude that in FHH with WNK4 mutations, with time all affected subjects will apparently develop hypertension. Hypercalciuria accompanies hyperkalemia, and both precede hypertension. Based on the recent findings that WNK4 regulates the renal outer medullary potassium channel as well as epithelial Cl/base exchanger and the Na-K-2Cl cotransporter, we suggest that WNK4 interacts with a calcium channel or transporter. (J Clin Endocrinol Metab 89: 4025–4030, 2004)

Antiphospholipid antibody syndrome (APS) is associated with adverse pregnancy outcomes and maternal complications including thrombotic events and early pre-eclampsia. HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets) represents a unique form in the spectrum of pre-eclampsia. This report describes four patients with pregnancy-associated hepatic infarctions. All four had APS and HELLP syndrome, which was complete in one patient and incomplete in three patients, with elevated liver enzymes in all, and either thrombocytopenia or hemolysis in two. In the literature, we found descriptions of an additional 24 patients who had 26 pregnancies with concomitant hepatic infarction. Of the total 28 patients, anticardiolipin antibodies (aCL) and/or lupus anticoagulant (LAC) were assessed in 16 patients, out of whom 15 were found to be positive. Hepatic infartction during pregnancy was associated almost always with APS, with HELLP (2/3 complete, 1/3 incomplete), and only in one-third of the pregnancies with pre-eclampsia (PE).

Mutations in WNK kinases cause pseudohypoaldosteronism type II (PHA II) and may represent a novel signaling pathway regulating blood pressure and K(+) and H(+) homeostasis. PHA II is an autosomal dominant disorder characterized by hypertension, hyperkalemia, and metabolic acidosis, with normal glomerular filtration rate. Thiazide diuretics correct all abnormalities. Inactivating mutations in the thiazide-sensitive NaCl cotransporter cause Gitelman syndrome, featuring hypotension, hypokalemia, and metabolic alkalosis plus hypocalciuria and hypomagnesemia. We investigated whether hypercalciuria and hypermagnesemia occurred in a large family with PHA II. Eight affected and eight unaffected members of a PHA II family with the Q565E WNK 4 mutation were studied. In affected members blood and urinary chemistry were measured on and off hydrochlorothiazide (HCTZ), and bone mineral density was determined. Marked sensitivity to HCTZ was found. A mean dose of 20 mg/d reduced mean blood pressure in the six hypertensive subjects by 54.3 (systolic) and 24.5 (diastolic) mm Hg. In affected subjects, HCTZ reduced mean serum K(+) by 1.12 mmol/liter, mean serum Cl(-) by 6.2 mmol/liter, and mean urinary calcium by 65% and elevated mean serum calcium by 0.11 mmol/liter and mean serum urate by 118 micromol/liter. Compared with the literature, this represents an increase of 6-7 in HCTZ potency. Affected members had normomagnesemia, hypercalciuria (336 +/- 113 vs. 155 +/- 39 mg/d in unaffected relatives, P = 0.0002), and decreased bone mineral density. In PHA II the observed marked sensitivity to thiazides and the hypercalciuria are consistent with increased NaCl cotransporter activity. PHA II may serve as a model to investigate thiazides' beneficial effects and side effects.

SummaryFifty-seven pregnancies in women with antiphospholipid syndrome (APS) are presented. These were treated with s.c. enoxaparin and low dose aspirin. In fourteen pregnancies warfarin was prescribed between weeks 15-34 (warfarin group). The decision to switch to warfarin depended on a morbidity score, and the patient’s consent. Neither teratogenicity nor significant maternal, fetal or neonatal hemorrhage was observed. Despite the higher pretreatment morbidity score of the warfarin group, the live birth rate was high in both groups: 86% in the warfarin group and 87% in the non-warfarin group. There was no significant difference in week of delivery, birth weight, or incidence of thrombosis between the groups. The study demonstrates the efficacy and safety of anticoagulants during pregnancy. The use of LMWH in pregnant women with APS not being moot, warfarin might be justified in selected patients.

Systemic lupus erythematosus (SLE) is characterized by the finding of ample serum autoantibodies. The role and the origin of many of these antibodies are still obscure. The aim of this work was to study the occurrence of anti-insulin antibodies (AIA) in SLE, and to postulate, based on AIA determination, on the mechanisms involved in the production of some autoantibodies in SLE. IgG and IgM AIA, anti-DNA antibodies (ADA) and anti-tetanus toxoid antibodies (ATA) were determined using ELISA in sera and B-lymphocytes culture media of 24 SLE patients, 10 healthy controls and 19 insulin-dependent diabetes mellitus (IDDM) patients. B and T-lymphocytes were isolated using Ficoll gradient, depleted of T-cells using cyclosporin A, EBV infected and grown in medium. The frequencies of IgM-AIA and IgG-ADA were higher in SLE patients than in healthy controls (P

Infection is the major cause of morbidity and mortality in systemic lupus etythematosus (SLE). Although various fungi account for a substantial number of these lethal infections, aspergillosis, an important opportunistic infection in immunosuppressed patients, is described rarely. Only 23 cases have been reported in the English-language medical literature. Risk factors for acquiring aspergillosis in these patients were high grade disease activity, granulocytopenia, use of steroids and other immunosuppressive treatment and presence of bacterial infection. The diagnosis in most patients was delayed and they died. Here, we describe three SLE patients with invasive aspergillosis. Features of our patients' diseases were similar to those reported previously. Aspergillosis appeared while they had active SLE treated with high dose corticosteroids. In 2 patients the fungal infection was systemic and diagnosed post mortem. Both were leukopenic and had concurrent bacterial infection and one received amphotericin B prior to death. In the third, the infection was localized to a transplanted kidney and was cured by nephrectomy. Aspergillosis should be suspected in patients with active SLE, who are immunocompromised and sustain concomitant bacterial infections. The currently poor prognosis may be improved with mote aggressive diagnostic investigation and treatment.

S 62 HIGH ANTIPHOSPHOLIPID ANTIBODY TITERS ARE ASSOCIATED WITH ADVE PREGNANCY OUTCOME IN WOMEN WITH ANTIPHOSPHOLIPID ANTIBO SYNDROME MICHAL J. SIMCHEN, RACHEL PAUZNER, GUY ROFE, EYAL SCHIFF, MORDECHAI DULITZKI, Sheba Medical Center, Tel Aviv University, Obstetrics and Gynecology, Ramat Gan, Israel, Sheba Medical Center, Tel Aviv University, Internal Medicine, Rheumatology, Ramat Gan, Israel, Sheba Medical Center, Tel-Aviv University, Ramat Gan, Israel OBJECTIVE: To investigate whether, in patients with antiphospholipid antibody syndrome (APS), high antibody titers predict adverse pregnancy outcome. STUDY DESIGN: Women diagnosed with APS according to strict clinical and laboratory criteria were prospectively followed in pregnancy. Lupus anticoagulant, anticardiolipin antibodies and Beta-2 Glycoprotein 1 levels were measured prior to pregnancy. Women with antibody titers more than 4 times upper limit of normal were termed High Titer (HT) group, while women with lower positive antibody titers were considered Low Titer (LT) group. All women were treated with LMWH 0.7-1 mg/kg/day and aspirin 100 mg daily. Adverse pregnancy outcomes included fetal/neonatal loss, significantly premature birth 32 weeks= gestation, and intrauterine growth restriction (IUGR, 10th percentile). RESULTS: 51 women in 55 pregnancies were prospectively followed, 20 in the HT and 35 in the LT groups. 35% of HT women and 11.4% of LT women had triple antibody positivity (p 0.07). The risks of pregnancy loss, delivery 32 weeks and/or IUGR were all significantly more common in the HT as compared with the LT group. Moreover, among women with high titers, only 35% of pregnancies culminated in appropriately grown, liveborn infants 32 wks gestation, as compared with 77% of pregnancies with low titers (OR 0.17, 95% CI 0.05-0.53). The 2 groups were similar in the proportion of previous pregnancy losses, previous thromboembolic events, primary/secondary APS and concurrent genetic thrombophilias. CONCLUSION: In women with antiphospholipid syndrome, high antibody titers prior to pregnancy define a unique and extremely high-risk group for adverse pregnancy outcome. These women need special prenatal consultation and tight prenatal care.

SummarySixty-six SLE patients were studied for the presence of lupus type circulating anticoagulant. Forty-nine percent of them showed activity of this anticoagulant. The sensitivity of various coagulation tests was compared. Recalcification time was found to be the most sensitive screening test and the kaolin clotting time mixture test, the best for determining the presence of the anticoagulant.Tissue thromboplastin inhibition test detected only half of the patients in whom the anticoagulant was found by recalcification time and kaolin clotting time mixture test.APTT, using 2 different reagents, resulted in 73% and 52% false negatives. A numerical index for determining the presence of the anticoagulant and its quantitative evaluation is suggested.The association between thromboembolic events, recurrent abortions and the different coagulation tests is shown.

An awake patient presented with central neurogenic hyperventilation induced by a cerebral tumor. Corticosteroid therapy and brain irradiation while the patient was anesthetized and respiration controlled under pancuronium-induced respiratory paralysis were followed by tumor regression and resolution of hyperventilation. Recurrence of tumor 6 weeks later was not accompanied by recurrence of hyperventilation. Cytologic study of cerebrospinal fluid revealed B-cell lymphoma. This patient brings to 10 the number of cases recorded with tumor-induced central neurogenic hyperventilation. Five of the eight patients with known tumor histology had a primary cerebral lymphoma, a rare neoplasm that comprises only 1% of all intracranial neoplasms. The disproportionately high frequency of central neurogenic hyperventilation in patients with cerebral lymphoma has therapeutic implications that are briefly reviewed.

Two patients with hyponatremia (130 mEq/l and 122 mEq/l, respectively), and rickettsial disease are described. The causes of hyponatremia were attributed to rickettsial vasculitis and increased capillary permeability in the first patient and to the syndrome of inappropriate anti-diuretic hormone (ADH) secretion in the second patient. The differentiation between the mechanisms was established by measurement of urinary sodium excretion which was low in the first patient (7 mEq/l) and high in the second patient (60 mEq/l), and levels of ADH that were inappropriately high in the second patient (7-9 pg/ml) in the presence of low plasma osmolality. The differentiation between these causes of hyponatremia has important therapeutic implications.

• Between February and June 1985, 40 military personnel were hospitalized because of measles. Diagnosis in all patients was entirely clinical, and serologic investigations were noncontributory. A transient disturbance in liver function occurred in 70% of patients, and its extent correlated with duration of fever and disease complications. Spontaneously resolving, measles-specific hypocalcemia, which was not associated with hepatic dysfunction, was noted in about one third of the patients. All these patients were asymptomatic, except one patient who developed tetany. The pathophysiologic basis for the hypocalcemia is still unknown. The disease course in three previously immunized patients was benign and uncomplicated. ( Arch Intern Med 1987;147:1111-1113)