The fine line between Takayasu arteritis and giant cell arteritis.

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.

Clinical characteristics and risk factors for low dose methotrexate toxicity: a cohort of 28 patients.

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.

Epstein-Barr virus antibodies mark systemic lupus erythematosus and scleroderma patients negative for anti-DNA.

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.

The limited role of MRI in long-term follow-up of patients with Takayasu's arteritis.

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.

High positive antibody titers and adverse pregnancy outcome in women with antiphospholipid syndrome.

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-ß2-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.

An antibody profile of systemic lupus erythematosus detected by antigen microarray.

SUMMARY: 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.

[Clinical-pathological conference: multiple pulmonary nodules in a 63 year old woman].

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. .

Outcome of patients having dermatomyositis admitted to the intensive care unit.

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.

Safety of IVF under anticoagulant therapy in patients at risk for thrombo-embolic events.

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.

Increased platelet deposition on extracellular matrix under flow conditions in patients with antiphospholipid syndrome who experience thrombotic events.

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.

Resolution of hypertension during pregnancy in familial hyperkalemia and hypertension with the WNK4 Q565E mutation.

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.

Hypercalciuria in familial hyperkalemia and hypertension accompanies hyperkalemia and precedes hypertension: description of a large family with the Q565E WNK4 mutation.

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 follow-up. 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.

Pseudohypoaldosteronism type II: marked sensitivity to thiazides, hypercalciuria, normomagnesemia, and low bone mineral density.

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.