Irena Litinsky

Autoantibodies profile of rheumatoid arthritis patients during treatment with infliximab

Purpose: Therapy with TNFα blocking agents has been associated with increased rate of anti-nuclear antibodies (ANA) and rare cases of lupus like syndromes. Our aim was to prospectively analyze a wide array of autoantibodies in rheumatoid arthritis (RA) patients before and 14 weeks after starting infliximab. Material and Methods: In this study, 26 consecutive active RA patients participated. All treated with infliximab at a dosage of 3 mg/kg on week 0, 2, 6 and every 8 weeks, along with weekly low dose methotrexate. Patients were evaluated at week 0 and 14. Clinical assessment included the number of tender and swollen joints, duration of morning stiffness, adverse events (AE) (including SLE-like) and ESR. Sera were collected before the 1st infusion of infliximab at week 0 and 14. The autoantibodies studied were: fluorescent ANA, anti-double-stranded-DNA (anti-ds-DNA), IgG and IgM anti-cardiolipin (ACA), anti-histone- H1 and C (H1, H2A, H2B, H3, H4), anti-SSA, -SSB, -ENA, -scleroderma 70, -thyroid peroxidase (TPO) and -neutrophilic cytoplasmatic (ANCA) antibodies. Results: Of 26 patients, 17 were women. A significant decrease in duration of morning stiffness, number of tender and swollen joints and ESR were observed between week 0 and 14. During follow up (mean of 20.5±7.3 months), 9 patients stopped infliximab due to inefficacy or AE (most of them after the 4th infusion). Two patients developed lupus-like phenomena. ANA was found positive at baseline in 7 out of 26 patients. In 5 of them, an increase in the titer of ANA was observed at week 14. ANA negative turned positive for 8 patients. A significant increase of anti-cardiolipin (ACA)-IgM levels was observed in 8 patients and of ACA-IgG in 6, in parallel with ANA seroconversion. The mean level of anti-double-stranded-DNA (anti-ds-DNA) -IgG significantly increased from 66±33 to 93±68 IU/ml, in 4 patients to pathological levels. Four patients demonstrated an increase in anti-histone H1. Levels of ANCA, anti-ENA, -SSA, -SSB, -RNP, -scleroderma70 and -thyroid peroxidase (TPO) were negative in all patients and remained unchanged during the study. Cessation of treatment with infliximab was found to be associated with the appearance of ANA. Conclusion: An increased titer or a new appearance of ANA was observed in 12 out of 26 patients. The main autoantibodies found were anti-ds-DNA, ACA-IgM and -IgG and anti-histone. In our cohort, the appearance of some autoantibodies seemed to predict late cessation of treatment.

Cardiac dysfunction in patients with systemic lupus erythematosus and antiphospholipid syndrome

Objective: To comparatively assess the parameters of systolic and diastolic cardiac function in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Methods: Consecutive patients (n = 74) who were free of cardiovascular symptoms were divided into four groups: (1) SLE (n = 23); (2) SLE with antiphospholipid antibodies (aPL; n = 18); (3) SLE with APS (n = 20); and (4) primary antiphospholipid syndrome (PAPS; n = 13). Pulsed, continuous, colour Doppler echocardiography, and M-mode and B-mode studies were performed. Results: Left ventricular end diastolic and end systolic dimensions were higher in SLE as compared with patients with PAPS (p = 0.022 and 0.022, respectively), with a trend towards a lower fractional shortening in SLE (p = 0.07), suggesting systolic dysfunction. Parameters of diastolic function were more impaired in patients with APS, reflected by lower left ventricular and right ventricular E wave to A wave (E:A) ratios in patients with APS (groups 3, 4) compared with those without APS (groups 1, 2; 1.15 (0.40) v 1.49 (0.43), p = 0.001 and 1.19 (0.31) v 1.49 (0.41), p = 0.001, respectively) and a more prolonged left ventricular isovolumic relaxation time (IVRT; 94.2 (24.6) v 84.4 (17) ms, respectively, p = 0.055). Patients with APS were older than those without APS (47.12 (14.86) v 34.29 (12.6), p = 0.0001). Patients with SLE were younger than those with PAPS (38.19 (14.68) v 48.53 (13.97), p = 0.023). Conclusion: Abnormal echocardiographic findings were detected frequently in asymptomatic patients with SLE or PAPS. Although patients with SLE were younger, left ventricular systolic function was more impaired in patients with SLE compared with those with PAPS, whereas left ventricular and right ventricular diastolic function, as reflected by IVRT and E:A ratios, were significantly more impaired in patients with APS.

Anemia, serum vitamin B12, and folic acid in patients with rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus

ObjectiveAlthough anemia is frequent in inflammatory rheumatic diseases, data regarding vitamin B12 status is scarce. The purpose of this study was to analyze the incidence and nature of B12 and folic acid (FA) deficiencies in a cohort of rheumatic patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and systemic lupus erythematosus (SLE).MethodsLevels of B12, FA, and parameters of anemia were recovered or examined in 276 outpatients. In those with recent findings of low serum B12 levels, further studies of serum homocysteine (Hcy) and urine methylmalonic acid (MMA) levels were performed.ResultsThe incidence of anemia was high: 49%, 46%, and 35%, in RA, SLE, and PsA, respectively. Low levels of serum B12 were also frequent (24%), with almost similar occurrence in the three disease groups. Deficiency in FA was rare (<5%). Mean levels of both vitamins did not differ significantly among the three groups. No correlation between serum B12 levels and anemia was found. In the 15 patients with recently detected low B12 levels, Hcy and MMA were evaluated before and following B12 therapy. In ten of them, baseline Hcy levels were high, while MMA was increased in one patient only. Response to B12 administration, i.e., a decrease in Hcy and/or MMA levels, was noticed in four patients only, suggesting that only 26% of the low-serum-B12 patients had true B12 deficiency.ConclusionsThe incidences of anemia and decreased serum B12 levels were high in these three groups of rheumatic patients. However, true tissue deficiency seems to be much rarer.

Usefulness of losartan, captopril, and furosemide in preventing nitrate tolerance and improving control of unstable angina pectoris

Sixty consecutive normotensive patients with unstable angina pectoris, who were on continuous intravenous isosorbide dinitrate (ISDN) treatment and had not previously received angiotensin II receptor antagonists, angiotensin-converting enzyme (ACE) inhibitors, or diuretics were randomly assigned to treatment groups receiving intravenous ISDN for 72 hours. No additional treatment was given to group A (n = 15). Captopril, in a test dose of 6.25 mg, and followed by 12.5 mg 3 times daily for 24 hours and 25 mg 3 times daily for the next 24 hours, was given to group B (n = 15). The same dose of captopril plus 40 mg of furosemide in the morning were given to group C (n = 15). Losartan, in a single dose of 25 mg/day and increased to 50 mg after 24 hours was given to group D (n = 15). Nitrate tolerance was evaluated at 24-hour intervals at trough levels of each of the drugs by administering intravenous ISDN (1 mg bolus dose every 4 minutes) and recording the total ISDN test dose required to decrease the mean arterial blood pressure by > or =10%. Treatment with continuous ISDN only (group A) induced nitrate tolerance. The ISDN (mean +/- SD) test dose was 3.5 +/- 1.8 mg at baseline, increasing to 4.9 +/- 2.4 mg at 24 hours, and 8.0 +/- 3.0 mg at 48 hours. The addition of increasing doses of captopril to the continuous ISDN treatment (group B) completely prevented nitrate tolerance. Losartan, however, did not attenuate nitrate tolerance at 24 hours and attenuated it only partially at 48 hours. The addition of furosemide to captopril had no further effect on nitrate tolerance. Of 15 patients in group A (ISDN only), 4 (27%) experienced recurrent ischemic events requiring urgent coronary catheterization. No such events were recorded in group B (captopril), but did occur in 1 patient in each of group C (captopril plus furosemide) and D (losartan) (p = 0.083). Thus, the addition of captopril to the ISDN treatment regimen prevented tolerance to nitrates and improved angina control with apparent safety. Losartan also decreased nitrate tolerance, although to a lesser extent, and also improved angina control. The addition of furosemide to captopril conferred no further benefit.

Impaired memory and learning abilities in patients with systemic lupus erythematosus as measured by the Rey Auditory Verbal Learning Test

Objective: The purpose of this study was to assess and characterise verbal memory impairment in patients with systemic lupus erythematosus (SLE) by the Rey Auditory Verbal Learning Test (Rey AVLT). Methods: 40 consecutive, unselected patients with SLE were evaluated with the Rey AVLT, a clinical and research tool for the study of multiple learning and memory measures. All patients were assessed for disease activity, damage, presence of antiphospholipid antibodies and depression. Findings were compared with those of 40 healthy controls matched for age, sex and education. Results: The study group included 40 patients with SLE (37 females, 3 males), median age 33 years (range 20–59), median disease duration 8 years (range 0.3–32). The median disease activity measured by the SLE Disease Activity Index (SLEDAI) was 4 (range 0–16). Median damage measured by the SLICC/ACR (Systemic Lupus International Collaborating Clinics/American College of Rheumatology) damage index score was 0 (range 0–4). Depression was detected in 16/40 patients. Several aspects of the memory domain, as measured by the Rey AVLT, were impaired in the SLE group, using analysis of variance with repeated measures. The learning curve of patients with SLE was significantly less steep compared with that of controls, (p = 0.036), the rate of words omitted from trial to trial was higher in the SLE group (p = 0.034) and retrieval was less efficient in SLE compared with controls (p = 0.004). The significance of these findings was maintained after omitting patients with stroke or depression. Conclusion: Learning ability was impaired in patients with SLE with a poor and inefficient learning strategy, as reflected by an impaired learning curve, repeated omissions and impaired retrieval. This pattern of memory deficit resembles that seen in patients with frontal lobe damage and warrants further localising brain studies.

Impaired diffusion tensor imaging findings in the corpus callosum and cingulum may underlie impaired learning and memory abilities in systemic lupus erythematosus.

Background Memory impairment is prevalent in systemic lupus erythematosus (SLE); however, its pathogenesis is unknown. In a previous functional magnetic resonance imaging (fMRI) study we demonstrated altered brain activity dynamics and less brain deactivation in patients with SLE as compared with healthy controls, when performing a learning and memory task. Our findings localized this impairment to the default mode network (DMN), and particularly to its anterior medial prefrontal cortex node. In addition, altered networking of the hippocampal subsystem of the DMN was seen in patients with SLE when performing this task, as well as atrophy of the left hippocampus. The present study aimed to search for a structural substrate for the altered recruitment pattern observed in fMRI studies using diffusion tensor imaging (DTI). Patients and methods Using DTI, we characterized brain diffusivity in 10 patients with SLE and nine healthy controls. Two tracts associated with the DMN were reconstructed: the corpus callosum (CC) and the cingulum bundle. The CC was segmented according to the Witelson segmentation scheme and the cingulum was segmented into superior and descending bundles. Results A significant increase in mean diffusivity (MD) was seen in patients with SLE without neuropsychiatric SLE (NPSLE) as compared with healthy controls in all five segments of the CC (segment 1: p = 0.043; segment 2: p = 0.005; segment 3: p = 0.003; segment 4: p = 0.012; segment 5: p = 0.023) as well as in the descending portion of the left cingulum bundle (p = 0.026). Conclusions Increased MD values in the CC and the left cingulum may indicate impaired organization/reduced integrity of these tracts, which may underlie the abnormal pattern of brain activity recruitment of the DMN observed during a verbal learning and memory task. Taking into account the central role of the left hippocampus in verbal memory, the abnormal integrity of the left cingulum may contribute to the reduced performance of patients with SLE on verbal memory tasks.

Evoked potential studies in the antiphospholipid syndrome: differential diagnosis from multiple sclerosis

Background: The CNS manifestations of the antiphospholipid syndrome (APS) can mimic multiple sclerosis both clinically and radiologically. Objective: To compare evoked potential studies in APS patients and patients with multiple sclerosis with similar neurological disability. Methods: 30 APS patients with CNS manifestations and 33 patients with definite multiple sclerosis and similar neurological disability underwent studies of visual evoked potentials (VEP), somatosensory evoked potentials (SSEP) in the upper and lower limbs (UL, LL), and sympathetic skin responses (SSR) in the upper and lower limbs. Results: The neurological manifestations in the APS patients included stroke (n = 17), transient ischaemic attacks (n = 10), and severe headache with multiple white matter lesions on brain MRI (n = 3). Abnormal SSEP (LL), and SSR (UL; LL) were seen in APS patients (37%, 27%, and 30%, respectively) but VEP and UL SSEP were rarely abnormal (10% and 6%, respectively in APS v 58% and 33% in multiple sclerosis; p = 0.0005, p = 0.008). Mean VEP latencies were more prolonged in multiple sclerosis (116 ms v 101 ms, p<0.001). Only one APS patient had abnormal findings in all three evoked potential studies, compared with seven patients in the multiple sclerosis group (p = 0.04) Conclusions: Abnormal VEPs are uncommon in APS in contrast to multiple sclerosis. Coexisting abnormalities in all other evoked potentials were similarly rare in APS. In patients with brain MRI findings compatible either with multiple sclerosis or APS, normal evoked potential tests, and especially a normal VEP, may support the diagnosis of APS.

Dermonecrotic Loxoscelism in the Mediterranean Region

AbstractPublications on loxosceles spider bites in the Mediterranean region are scarce. This spider is frequently found in Israel and its bite may cause severe medical problem. We report on 11 patients who sustained such bites and required hospitalization between 1988 and 1997 in a regional hospital serving a population of 300,000. Most of them were bitten in the summer, 10 on the medial aspect of the arm or thigh. All patients exhibited the typical loxosceles skin lesion; systemic manifestations were evident in six. Seven patients were misdiagnosed. All were treated with antibiotics and eight with the addition of corticosteroids. Ten patients fully recovered within 2-3 weeks.The estimated incidence of severe dermonecrotic loxoscelism requiring hospitalization is 0.37 cases/100,000 population/year. It seems that the clinical course in our cases was somewhat milder than in other reported cases from the United States. This can possibly be attributed to the bite of Loxosceles rufescens, which is the prevaili...

The Changing Face of Spondyloarthropathies Under TNF α Blockade

Objectives Tumor necrosis factor alpha (TNF-α ) therapy has been implicated in the development of autoimmune diseases. Our aim was to describe three patients with spondyloarthropathies who responded to infliximab, a chimeric monoclonal antibody specific for TNF-α but developed new symptoms of spondyloarthropathies. In parallel, a review of the literature on psoriasis induced by TNF-α blockers was undertaken. Results The first patient had been suffering from ankylosing spondylitis (AS) for more than 12 years. Infliximab induced a remission of AS, but he developed overt Crohns disease two years after starting treatment. The second patient had AS for more than 20 years. Infliximab had an excellent effect on his AS, but he developed palmo-plantar psoriasis a few months after initiating therapy with the drug. The third patient, whose long-term and severe psoriasis had responded to infliximab developed peripheral arthritis. A review of the literature revealed 63 cases of psoriasis induced by TNF-α blockers (33 on Infliximab, 16 on Etanercept and 14 on Adalimumab). The underlying diseases were variable, including all the spectrum of conditions for which TNF-α blockers are indicated. Patients developed psoriasis after a mean duration of treatment of 11 months. Interstingly, a substantial proportion of patients continued treatment with TNF α blockers, the psoriasis improving in a majorityof cases under topical treatment only. Conclusion While Infliximab may change the course of spondyloarthropathy, depressing the original symptoms it may uncover other occult aspects of these diseases.