Rachel Pauzner

An antibody profile of systemic lupus erythematosus detected by antigen microarray

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 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.

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‐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.

Circulating Anticoagulant in Systemic Lupus erythematosus: Clinical Manifestations

The correlation between the presence of lupus circulating anticoagulant (LCA) and the incidence of thromboembolic phenomena was evaluated in 66 systemic lupus erythematosus (SLE) patients. Our criteria for the presence of LCA included an elevated LCA index and a prolonged recalcification time. Thirty-two patients (48%) fulfilled these criteria (group A). The incidence of thromboembolic phenomena, recurrent abortions and involvement of the nervous system was higher in group A patients than in SLE patients without LCA (group B). Moreover, 16 patients of group A who exhibited also a positive thromboplastin inhibition test associated with a markedly elevated LCA index, manifested higher incidence of severe thromboembolic phenomena. Early detection of LCA has important therapeutic implications. We suggest that the presence of LCA should be recognized as one of the criteria for the diagnosis of SLE.

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 Takayasus 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 Takayasus 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.

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.

Outcome of pregnancy in three patients with primaryantiphospholipid syndrome after stroke

OBJECTIVE Ischemic stroke is the most common neurological manifestation in patients 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 small doses 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.

Rickettsiosis-associated hyponatremia.

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. Es werden zwei Patienten beschrieben, die bei einer Rikkettsien-Infektion eine Hyponatriämie von 130 mÄq/l bzw. 122 mÄq/l entwickelten. Die Ursache für die Hyponatriämie wird beim ersten Patienten in einer Rikkettsien-Vaskulitis mit erhöhter Kapillarpermeabilität und beim zweiten in einer inadäquaten Sekretion von antidiuretischem Hormon (ADH) gesehen. Durch Messung der Natriumausscheidung im Urin war eine Differenzierung der beiden Pathomechanismen möglich: beim ersten Patienten war die Natriumausscheidung mit 7 mÄq/l niedrig und beim zweiten mit 60 mÄq/l hoch. Zudem waren die ADH-Spiegel beim zweiten Patienten mit 7–9 pg/ml bei geringer Plasmaosmolalität unangemessen hoch. Die Unterscheidung der Ursachen der Hyponatriämie hat wichtige therapeutische Konsequenzen.SummaryTwo 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.ZusammenfassungEs werden zwei Patienten beschrieben, die bei einer Rikkettsien-Infektion eine Hyponatriämie von 130 mÄq/l bzw. 122 mÄq/l entwickelten. Die Ursache für die Hyponatriämie wird beim ersten Patienten in einer Rikkettsien-Vaskulitis mit erhöhter Kapillarpermeabilität und beim zweiten in einer inadäquaten Sekretion von antidiuretischem Hormon (ADH) gesehen. Durch Messung der Natriumausscheidung im Urin war eine Differenzierung der beiden Pathomechanismen möglich: beim ersten Patienten war die Natriumausscheidung mit 7 mÄq/l niedrig und beim zweiten mit 60 mÄq/l hoch. Zudem waren die ADH-Spiegel beim zweiten Patienten mit 7–9 pg/ml bei geringer Plasmaosmolalität unangemessen hoch. Die Unterscheidung der Ursachen der Hyponatriämie hat wichtige therapeutische Konsequenzen.