Anti-inflammatory effects of infliximab and methotrexate on peripheral blood and synovial fluid mononuclear cells: ex vivo study.

OBJECTIVE: To investigate the effects of methotrexate (MTX) and the tumour necrosis factor inhibitor infliximab (IFX) on immune cells derived from peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) of inflammatory arthritis patients. METHOD: Phytohaemagglutinin (PHA)-induced proliferation of healthy donors' PBMCs and synovial intermediate monocytes (CD14+CD16+ cells) in SFMCs derived from psoriatic arthritis (PsA) and rheumatoid arthritis (RA) patients was determined by flow cytometry following co-culture with IFX and MTX. PHA-induced interferon-γ (IFN-γ) production in PBMCs was measured by enzyme-linked immunosorbent assay. The drugs' effect on mRNA expression in SFMCs was determined by quantitative polymerase chain reaction. RESULTS: The combination of IFX 10 µg/mL + MTX 0.1 µg/mL had the strongest inhibitory effect on PBMC proliferation (91%), followed by MTX 0.1 µg/mL (86%) and IFX 10 µg/mL (49%). In PHA-stimulated PBMCs, IFN-γ production was reduced by IFX 10 µg/mL, MTX 0.1 µg/mL, and IFX 10 µg/mL + MTX 0.1 µg/mL by 68%, 90%, and 85%, respectively. In SFMCs, IFX 10 µg/mL significantly reduced CD14+CD16+ cells compared to medium (PsA 54%, p < 0.01; RA 46%, p < 0.05), while MTX had no effect on this population. IFX + MTX led to a similar suppression of CD14+CD16+ cells as achieved by IFX alone. The drugs had different impacts on SFMC gene expression. CONCLUSION: Both IFX and MTX effectively inhibited PBMC proliferation and IFN-γ production, but only IFX reduced synovial monocytes and pro-inflammatory gene expression in SFMCs, suggesting a differential impact of IFX and MTX on critical inflammatory cell populations ex vivo.

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.

QuantiFERON-TB Gold in the identification of latent tuberculosis infection in rheumatoid arthritis: a pilot study.

OBJECTIVE: To compare the performance of QuantiFERON-TB Gold (QFT-G) with that of the tuberculin skin test (TST) in detecting latent tuberculosis (LTBI) among patients with rheumatoid arthritis (RA). PATIENTS AND METHODS: A total of 35 RA patients and 15 healthy controls underwent TST, QFT-G assays and chest X-ray and filled out a questionnaire on predisposing conditions for TB disease. Serum interferon gamma (IFN-gamma) levels were tested by an enzyme-linked immunosorbent assay. RESULTS: Forty-five per cent of RA patients had a TST > 5 mm vs. 26% in healthy controls. In the RA patients, QFT-G was positive in 11.4%, negative in 60% and indeterminate in 28.6%. The overall agreement between TST and QFT-G was significantly lower in the RA population than in controls (56% vs. 84%). No correlation was found between the use of prednisone, methotrexate and QFT-G results or agreement between TST and QFT-G. A low IFN-gamma level (<4 pg/ml) was found in 51.5% of the RA patients. No correlation was found between serum IFN-gamma levels and QFT-G results. CONCLUSION: The clinical significance of negative QFT-G in TST-positive patients with low TB risk remains to be assessed. The high rate of indeterminate results questions the clinical utility of QFT-G in the diagnosis of LTBI in RA patients.

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.

Vaccination against influenza in patients with rheumatoid arthritis: the effect of rituximab on the humoral response.

OBJECTIVE: To assess the effect of rituximab on the efficacy and safety of influenza virus vaccine in patients with rheumatoid arthritis (RA). METHODS: The study group comprised patients with RA treated with conventional disease-modifying drugs with or without rituximab. Split-virion inactivated vaccine containing 15 microg haemagglutinin/dose of B/Shanghai/361/02 (SHAN), A/New Caledonian/20/99 (NC) (H1N1) and A/California/7/04 (CAL) (H3N2) was used. Disease activity was assessed by the number of tender and swollen joints, duration of morning stiffness and evaluation of pain on the day of vaccination and 4 weeks later. CD19-positive cell levels were assessed in rituximab-treated patients. Haemagglutination inhibition (HI) antibodies were tested and response was defined as a greater than fourfold rise 4 weeks after vaccination or seroconversion in patients with a non-protective baseline level of antibodies (<1/40). Geometric mean titres (GMT) were calculated in all subjects. RESULTS: The participants were divided into three groups: RA (n = 29, aged 64 (12) years), rituximab-treated RA (n = 14, aged 53 (15) years) and healthy controls (n = 21, aged 58 (15) years). All baseline protective levels of HI antibodies and GMT were similar. Four weeks after vaccination, there was a significant increase in GMT for NC and CAL antigens in all subjects, but not for the SHAN antigen in the rituximab group. In rituximab-treated patients, the percentage of responders was low for all three antigens tested, achieving statistical significance for the CAL antigen. Measures of disease activity remained unchanged. CONCLUSION: Influenza virus vaccine generated a humoral response in all study patients with RA and controls. Although the response was significantly lower among rituximab-treated patients, treatment with rituximab does not preclude administration of vaccination against influenza.

Pulmonary dysfunction in systemic lupus erythematosus and anti-phospholipid syndrome patients.

OBJECTIVE: To assess and compare parameters of pulmonary function in systemic lupus erythematosus (SLE) and anti-phospholipid syndrome (APS) patients. METHODS: Consecutive patients (n = 74) who were free of respiratory symptoms were divided into four groups: 1) SLE (n = 23); 2) SLE with anti-phospholipid antibodies (aPL) (n = 18); 3) SLE with APS (n = 20); and 4) primary APS (PAPS) (n = 13). Pulmonary function testing, single breath diffusion capacity of carbon monoxide (DLCO/SB) and echocardiography studies were performed. Induced sputum cytology was analysed. RESULTS: Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and DLCO were significantly reduced in SLE compared to PAPS patients (p = 0.039; p = 0.017; p = 0.029, respectively). Elevated pulmonary arterial pressure was observed in two patients with SLE and aPL and in two with SLE and APS. Lymphocyte and eosinophil counts in induced sputum showed no significant differences; however, a trend towards lower CD4 counts in SLE vs. PAPS was noted (p = 0.086), while in patients with both SLE and APS, a low CD4/CD8 ratio was seen. Patients with APS were older than patients without APS (47.12+/-14.86 vs. 34.29+/-12.6, p = 0.0001), while SLE patients were younger than PAPS patients (38.19+/-14.68 vs. 48.53+/-13.97, p = 0.023). CONCLUSION: Abnormal pulmonary functions tests were detected frequently in asymptomatic patients with SLE or PAPS. Although SLE patients were younger, pulmonary function was significantly more impaired in SLE as compared to PAPS patients.

Vaccination against influenza in rheumatoid arthritis: the effect of disease modifying drugs, including TNF alpha blockers.

OBJECTIVE: To assess the efficacy and safety of vaccination against influenza virus in patients with rheumatoid arthritis, with special emphasis on the effect of disease modifying antirheumatic drugs (DMARDs), including tumour necrosis factor alpha (TNFalpha) blockers. METHODS: 82 rheumatoid patients and 30 healthy controls were vaccinated with a split-virion inactivated vaccine containing 15 mug haemagglutinin (HA) per dose of each of B/Hong Kong/330/2001 (HK), A/Panama/2007/99 (PAN), and A/New Caledonian/20/99 (NC). Disease activity was assessed by tender and swollen joint count, morning stiffness, evaluation of pain, Health Assessment Questionnaire, ESR, and C reactive protein on the day of vaccination and six weeks later. Haemagglutination inhibiting (HI) antibodies were tested by a standard WHO procedure. Response was defined as a fourfold or more rise in HI antibodies six weeks after vaccination, or seroconversion in patients with a non-protective baseline level of antibodies (<1/40). Geometric mean titres (GMT) were calculated to assess the immunity of the whole group. RESULTS: Six weeks after vaccination, a significant increase in GMT for each antigen was observed in both groups, this being higher in the healthy group for HK (p=0.004). The percentage of responders was lower in rheumatoid patients than healthy controls (significant for HK). The percentage of responders was not affected by prednisone or any DMARD, including methotrexate, infliximab, and etanercept. Indices of disease activity remained unchanged. CONCLUSIONS: Influenza virus vaccine generated a good humoral response in rheumatoid patients, although lower than in healthy controls. The response was not affected by the use of prednisone or DMARDs.

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.

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.

Unrecognized major bleeding following thrombolysis for acute myocardial infarction presenting with syncope.

Complete atrioventricular block and syncope sometimes are the presenting signs of acute myocardial infarction. In a presyncopal attempt to assume sitting position, the patient may fall and suffer consequent trauma. Once in hospital, this sequence of events may be overlooked by both the patient and admitting physicians. Moreover, physical examination initially may not be revealing. We report on two such patients who developed massive subcutaneous bleeding following thrombolytic and heparin treatment. We conclude that these patients constitute a specific group with a relatively high risk of trauma and bleeding at the gluteal region following thrombolytic therapy. Special attention must be given to these patients.

[Bronchiolitis obliterans organizing pneumonia].

Bronchiolitis obliterans organizing pneumonia (BOOP) is an uncommon condition of unknown etiology which often responds to corticosteroids. It is characterized by cough, patchy pulmonary infiltrations and intra-alveolar organizing fibrosis. We report a 45-year-old man and a 70-year-old woman with BOOP and elevated liver enzymes. Corticosteroid therapy led to complete recovery.