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Objective Subclinical myocardial dysfunction has been reported to occur early in systemic lupus erythematous (SLE). The study aim was to search for biomarkers of subclinical myocardial dysfunction which may correlate with disease activity in SLE patients. Methods This is a prospective, controlled, cross-sectional study of 57 consecutive patients with SLE and 18 controls. Serum samples were obtained to determine serum soluble ST2 (sST2), CXCL-10 and high-sensitivity troponin (hs-troponin) levels. All participants underwent an echocardiographic tissue Doppler study. Results sST2, CXCL-10 and hs-troponin levels were higher in patients with higher SLE disease activity (SLEDAI). sST2 and CXCL-10 levels were higher in patients with more disease damage as measured by the SLE damage index. Measures of diastolic dysfunction, as assessed by echocardiographic tissue Doppler negatively correlated with log CXCL-10: including E/A; E/e′lateral and E/e′septal, while E/e′ positively correlated with CXCL-10. Diastolic dysfunction parameters also correlated with log sST2 levels, a negative correlation was seen with E/e′lateral and a positive correlation was seen with E/e′. Systolic dysfunction parameters positively correlated with hs-troponin: LVED, LVES, IVS, LVMASS and LVMASS index. In a multivariate analysis, sST2 and CXCL-10 were found to be significantly different in SLE vs. healthy controls, independent of each other and independent of cardiovascular risk factors. Conclusions Soluble ST2 and CXCL-10 are markers of disease activity and accrued damage in SLE and may serve as sensitive biomarkers for detection of subclinical diastolic dysfunction, independent of traditional cardiovascular risk factors.

Background:Inflammatory joint diseases, such as psoriatic arthritis (PsA), are frequently treated by biologics. Assessment of treatment efficacy is based upon change in clinical activity scores and in tender and swollen joint counts. Although the response to these agents may be attributed to their central anti-inflammatory effects, synovial response may be operating in parallel. The potential beneficial role of intra-articular injection of tumor necrosis factor (TNF) blockers compared to glucocorticoids (GCs) in reducing synovitis was shown by means of clinical and instrumental validated measures (1). The inflamed synovial fluid is rich in mononuclear cells, however, the different mode of action of the in vitro response of these cells to drugs may contribute to the understanding of cellular response to therapeutic agents in central as opposed to peripheral compartments.Objectives:To evaluate the effect of biologics used in the management of PsA on synovial fluid mononuclear cells (SFMCs) in vitro, and to compare their modes of action to GCs that are used to locally alleviate synovial inflammation.Methods:SFMCs were obtained from PsA patients (n=11) during therapeutic knee arthrocentesis. The cells were cultured in vitro for 7 days in the presence of biologics (adalimumab, infliximab, secukinumab and ustekinumab, 10ug/ml) and GCs (betamethasone and methylprednisolone, 1 ug/ml and 10ug/ml) or medium as control. Levels of the secreted TNF were measured by ELISA. Changes in %CD14+CD16+ monocytes were analyzed by flow cytometry.Results:Both TNF inhibitors (adalimumab pp=0.0003) and GCs (betamethasone and methylprednisolone at 1ug/ml pp+CD16+ SFMCs derived from PsA patients (n=11) were significantly reduced by TNF inhibitors (p=0.0003) compared to medium, however, other biologics and GCs did not display similar activity (Fig. 1B).Figure 1.Both TNF inhibitors and GCs block TNF secretion but exhibit different activity on inflammatory CD14+CD16+ monocytes derived from SFMCs of PsA patients. SFMCs were co-cultured for 7 days in the presence of adalimumab, infliximab, secukinumab and ustekinumab at 10ug/ml or with betamethasone and methylprednisolone at 1ug/ml and 10ug/ml. Medium alone was used as a control. (A) Culture supernatants were analyzed for TNF levels by ELISA (n=8). (B) Cells were analyzed for %CD14+CD16+ monocytes by flow cytometry (n=11). All p values were calculated by the non-parametric one-way ANOVA Kruskal-Wallis test and Dunn’s multiple comparison test, *ppp=0.0003.Conclusion:Our data demonstrated marked activity mediated by TNF inhibitors in comparison with other biologics tested for their ability to suppress TNF secretion and inflammatory CD14+CD16+ monocytes. In contrast, GCs suppressed TNF secretion but did not significantly change the proportion of inflammatory CD14+CD16+ monocytes. These findings suggest an additional mechanism of action exerted directly by TNF inhibitors on synovial monocytes and which differs from that of GCs. These results warrant further studies of the therapeutic potential of local peripheral activity of TNF inhibitors for clinical application.Reference:[1]Carubbi F, Zugaro L, Cipriani P, Conchiglia A, Gregori L, Danniballe C, et al. Safety and efficacy of intra-articular anti-tumor necrosis factor alpha agents compared to corticosteroids in a treat-to-target strategy in patients with inflammatory arthritis and monoarthritis flare. Int J Immunopathol Pharmacol. 2016;29:252-66.Disclosure of Interests:None declared

Objective To evaluate the prevalence of sacroiliitis, the radiographic hallmark of inflammatory spondyloarthropathy, among patients diagnosed with fibromyalgia syndrome (FMS), using the current Assessment of SpondyloArthritis International Society (ASAS) criteria and magnetic resonance imaging. Methods Patients experiencing FMS (American College of Rheumatology 1990 criteria) were interviewed regarding the presence of spondyloarthritis (SpA) features and underwent HLA–B27 testing, C-reactive protein (CRP) level measurement, and magnetic resonance imaging examinations of the sacroiliac joints. FMS severity was assessed by the Fibromyalgia Impact Questionnaire and the Short Form 36 health survey. SpA severity was assessed by the Bath Ankylosing Spondylitis Disease Activity Index. Results Sacroiliitis was demonstrated among 8 patients (8.1%) and ASAS criteria for diagnosis of axial SpA were met in 10 patients (10.2%). Imaging changes suggestive of inflammatory involvement (e.g., erosions and subchondral sclerosis) were demonstrated in 15 patients (17%) and 22 patients (25%), respectively. The diagnosis of axial SpA was positively correlated with increased CRP level and with physical role limitation at recruitment. Conclusion Imaging changes suggestive of axial SpA were common among patients with a diagnosis of FMS. These findings suggest that FMS may mask an underlying axial SpA, a diagnosis with important therapeutic implications. Physicians involved in the management of FMS should remain vigilant to the possibility of underlying inflammatory disorders and actively search for such comorbidities.

Rheumatoid arthritis (RA) patients have many therapeutic options; however, tools to predict individual patient response are limited. The Genefron personal diagnostic kit, developed by analyzing large datasets, utilizes selected interferon stimulated gene expressions to predict treatment response. This study evaluates the kit's prediction accuracy of individual RA patients' response to tumor necrosis alpha (TNFα) blockers.A retrospective analysis was performed on RA patients reported in published datasets. A prospective analysis assessed RA patients, before and 3 months after starting a TNFα blocker. Clinical response was evaluated according to EULAR response criteria. Blood samples were obtained before starting treatment and were analyzed utilizing the kit which measures expression levels of selected genes by quantitative real time polymerase chain reaction (PCR). ROC analysis was applied to the published datasets and the prospective data.The Genefron kit analysis of retrospective data predicted the response to a TNFα blocker in 53 of 61 RA patients (86.8% accuracy). In the prospective analysis, the kit predicted the response in 16 of 18 patients (89% accuracy) achieving a EULAR moderate response, and in 15 of 18 patients achieving a EULAR good response (83.3% accuracy). ROC analysis applied to the two published datasets yielded an AUC of 0.89. ROC analysis applied to the prospective data yielded an AUC of 0.83 (sensitivity - 100%, specificity - 75%) The statistical power obtained in the prospective study was .9.The diagnostic kit predicted the response to TNFα blockers in a high percentage of patients assessed retrospectively or prospectively. This personal kit may guide selection of a suitable biological drug for the individual RA patient.

The aim of this study was to evaluate the presence of autoantibodies to cyclic citrullinated synthetic peptides (ACPAs) in the sputum of patients with long-standing rheumatoid arthritis (RA).Nineteen consecutive RA patients and 16 age- and sex-matched control subjects participated in this cross-sectional study. All underwent complete lung function tests and provided induced sputum. Antibodies to citrullinated (CitP) and the corresponding norleucine-containing (NorP) peptides in the sputum of the RA patients and control subjects, as well as in the serum of the RA patients, were determined by enzyme-linked immunosorbent assay.Patients with RA had the following characteristics: mean disease duration of 12 years, Disease Activity Score for 28 joints of 3.44, and Sharp-van der Heijde score of 57.5. Ten of the 19 RA patients showed high titers of ACPAs in their sera. Four of the seropositive (40%), none of the seronegative RA patients, and only 1 of the control subjects showed detectable levels of ACPAs in their sputum. The ratio between the reactivity with CitP and NorP peptides in the sputum was significantly higher in RA sputum than in control sputum (1.33 ± 1.2 vs. 0.64 ± 0.14, P = 0.02). A positive correlation was found between sputum ACPAs and age, serum ACPAs, sputum anti-NorP, serum anti-CitP/NorP reactivity ratio, and the proportion of neutrophils and lymphocytes in the sputum. No significant correlation was found between sputum ACPAs and disease severity, history of smoking, lung function tests, or treatment for RA.Anticitrullinated protein/peptide antibodies can be detected in the sputum of RA patients and are correlated with the presence in the serum.

Galectin-3 is a β-galactoside-binding lectin that plays an important role in the modulation of immune responses. It has been shown to aggravate joint inflammation and destruction in experimental arthritis. We investigated the role of galectin-3 in TLR-induced cell activation in human synovial fibroblasts (SF) in order to better understand the mechanism(s) of the proinflammatory function of galectin-3 in arthritis. Galectin-3 expression in SF obtained from rheumatoid arthritis and osteoarthritis patients was inhibited by siRNA mediated gene-knockdown. Galectin-3 was also inhibited with modified citrus pectin (MCP), a polysaccharide galectin-3 ligand. Galectin-3 knockdown inhibited TLR-2, -3 and -4-induced IL-6 secretion, but not TLR-2, -3 and -4-mediated matrix metalloproteinase-3 or CC chemokine ligand-5 secretion. When the SF were stimulated with phorbol 12-myristate 13-acetate, a protein kinase C activator that bypasses the membranal receptors, galectin-3 knockdown no longer influenced IL-6 secretion. MCP reduced IL-6 levels in a dose-dependent manner. Our results indicate that galectin-3 is a positive sensor-regulator of TLR-induced IL-6 secretion in human synovial fibroblasts, thus adding new insights into the mechanisms by which galectin-3 augments synovial inflammation. These findings corroborate the potential role of glycan inhibitors of galectin-3 as a therapeutic approach for the treatment of inflammatory arthritis.

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.

Background Rheumatoid arthritis (RA) patients have many therapeutic options. However, there are limited tools to predict the individual patient9s response to therapy. The Genefron personal diagnostic kit (IFR 300) has been developed based on analysis of large databases to select interferon stimulated gene (ISG) expressions which could predict response to a biologic agent Objectives This study aims to evaluate the ability of the Genefron diagnostic kit to predict the individual RA patient response to TNFα blockers. Methods Two separate analyses were performed, one retrospective and one prospective analysis. The response of 61 RA patients reported in 2 published data sets was analyzed retrospectively utilizing the Genefron kit. In addition, 18 patients with RA were assessed prospectively, before and 3 months after starting treatment with a TNFα blocker. Clinical assessment included swollen and tender joint counts, patient and physician assessments of disease activity. Patients9 blood samples were obtained before administration of the TNFα blocker and were analyzed utilizing the Genefron diagnostic kit which measures expression levels of selected genes by quantitative real time PCR. Results Genefron kit analysis of retrospective data correctly predicted the response to a TNFα blocker in 53 of 61 RA patients (accuracy - 86.8%). In the prospective analysis 6 patients achieved a moderate EULAR response, 6 achieved a good EULAR response and 6 did not respond. According to the EULAR moderate response, the Genefron diagnostic kit predicted the response correctly in 16 of 18 patients (accuracy-89%, sensitivity -100%, specificity - 67%). According to the EULAR good response, the kit predicted the response correctly in 15 of 18 patients (accuracy - 83.3%, sensitivity - 100%, specificity - 75%). Conclusions The Genefron diagnostic kit predicted the response to TNFα blockers in a high percentage of RA patients assessed either retrospectively or prospectively in a real life setting. This personal diagnostic kit has the ability to guide selection of a suitable biological drug for the individual RA patient Disclosure of Interest None declared

The objective of the study was to combine ultrasonographic (US) with clinical findings for comparing the effect of adalimumab (ADA) to methotrexate (MTX) on the thickness of tendons and enthesis in psoriatic arthritis (PsA) patients. Forty-three consecutive PsA patients were examined at baseline and after 6 and 12 weeks of treatment with ADA or MTX. The US assessment included thickness measurement of the extensor (ET) and flexor tendons (FT) of the second and third finger of both hands, plantar aponeurosis (PA) and the Achilles tendon (AT) bilaterally. Disease activity (DA) was assessed by the number of tender (TJ) and swollen joints (SJ), the number of inflamed enthesis (IE), pain assessment (PAI), and patient (PDAI) and physician (PHDAI) disease activity evaluations by visual activity score (VAS). Nineteen patients received MTX and 24 patients received ADA. All DA parameters improved in both groups. A decrease in thickness of tendons and enthesis was observed only in the ADA group, reaching a level of significance for the left AT (p = 0.01), left PA (p = 0.007), the second left FT (p = 0.04) and the third ET (p = 0.04). ADA patients showed a trend towards a better response to treatment compared to MTX patients that reach significance at week 6 of treatment for the thickness of left AT (p = 0.04), left PA (p = 0.03), the number of TJ (p = 0.0136), PAI (p = 0.0028), and PDAI (p = 0.029). ADA treatment for PsA compared to MTX significantly improved signs of DA and several US parameters. US assessment of enthesis can be an additional useful tool in the monitoring of psoriatic enthesopathy.

Objective.To describe the Israeli experience of treating adult-onset Still’s disease (AOSD) with tocilizumab (TCZ).Methods.Israeli rheumatologists who treated AOSD with TCZ filled in questionnaires on symptoms, number of tender and swollen joints, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and dosage of prednisone at initial TCZ administration, after 6 months, and at the end of followup.Results.Nine male and 6 female patients, aged 33 ± 12 years, mean disease duration 9 years (range: 1–25) were identified. They had used a mean of 3.6 disease-modifying drugs, including 10 patients with tumor necrosis factor blockers. Intravenous TCZ 8 mg/kg was administered every 4 weeks (12 patients) or every 2 weeks (3 patients). All patients completed at least 6 months of treatment. The mean followup period was 15.7 ± 9 months. At the onset of therapy, despite the use of prednisone (27.6 ± 26.3 mg/d), all patients reported joint pain. Fever was reported in 9 patients, rash in 7, pleuritis in 3, and hepatitis in 2 before TCZ use, with mean ESR and CRP levels of 60 ± 28 mm/h and 11.6 ± 15 mg/dl, respectively. After 6 months of treatment and at the end of followup, the number of tender and swollen joints, the ESR and CRP levels, and the prednisone dosage decreased significantly. Only 2 patients still complained of mild arthralgias, and none reported systemic symptoms at the end of followup.Conclusion.TCZ 8 mg/kg was extremely efficacious in treating adult patients with refractory Still’s disease. Both TCZ and interleukin 1 blockade should be considered in the treatment algorithm of AOSD. Randomized controlled studies are needed to validate these findings.

BackgroundMemory impairment is prevalent in systemic lupus erythematosus (SLE); however, the pathogenesis is unknown.MethodsWe studied 12 patients with SLE without clinically overt neuropsychiatric manifestations and 11 matched healthy controls, aiming to characterize neural correlates of memory impairment, using structural and functional magnetic resonance imaging (MRI). The paradigm consisted of three encoding and free-recall cycles, allowing characterization of dynamics along consecutive retrieval attempts.ResultsDuring learning, patients with SLE and healthy controls showed brain activity changes in two principal networks, the default mode network (DMN) and the task-positive network (TPN). Patients with SLE demonstrated significantly less deactivation in the DMN and greater activation in the TPN, reflecting greater recruitment of both networks. The anterior medial prefrontal cortex (amPFC) of the DMN emerged as the only region where brain activity dynamics were altered both over the learning process ( p ConclusionsIncreased brain activation in patients with SLE during learning may reflect compensatory mechanisms to overcome memory impairment. Our findings localize this impairment to the amPFC, consistent with the behavioral pattern seen in SLE. Altered networking of the hippocampal subsystem of the DMN is consistent with hippocampal neuronal damage seen in SLE, and may reflect compensatory cortical reorganization to cope with dysfunction in these regions pivotal to mnemonic functions.

To evaluate the prevalence of sacroiliitis, the radiographic hallmark of inflammatory spondyloarthropathy, among patients diagnosed with fibromyalgia syndrome (FMS), using the current Assessment of SpondyloArthritis International Society (ASAS) criteria and magnetic resonance imaging.Patients experiencing FMS (American College of Rheumatology 1990 criteria) were interviewed regarding the presence of spondyloarthritis (SpA) features and underwent HLA-B27 testing, C-reactive protein (CRP) level measurement, and magnetic resonance imaging examinations of the sacroiliac joints. FMS severity was assessed by the Fibromyalgia Impact Questionnaire and the Short Form 36 health survey. SpA severity was assessed by the Bath Ankylosing Spondylitis Disease Activity Index.Sacroiliitis was demonstrated among 8 patients (8.1%) and ASAS criteria for diagnosis of axial SpA were met in 10 patients (10.2%). Imaging changes suggestive of inflammatory involvement (e.g., erosions and subchondral sclerosis) were demonstrated in 15 patients (17%) and 22 patients (25%), respectively. The diagnosis of axial SpA was positively correlated with increased CRP level and with physical role limitation at recruitment.Imaging changes suggestive of axial SpA were common among patients with a diagnosis of FMS. These findings suggest that FMS may mask an underlying axial SpA, a diagnosis with important therapeutic implications. Physicians involved in the management of FMS should remain vigilant to the possibility of underlying inflammatory disorders and actively search for such comorbidities.

The flourishing online press in Israel and its implications for Israeli society are assessed according to a four-stage media development model (penetration, institutionalization, self-defence and adaptation). During the first decade of the current millennium, the online press became entrenched, shifting from the penetration stage to the institutionalization stage. Since then, the printed press has been showing signs of adaptation to the new online press. It seems that the powerful media conglomerates have again succeeded in intensifying their hold on the new platform, leaving us with a new journalism but the old hegemony.

To study the prevalence of rheumatic diseases in Israel by applying the Community Oriented Program for the Control of Rheumatic Diseases core questionnaire (CCQ).Representative samples (total of 2520 people) of the Israeli Jewish population aged ≥20 were surveyed for rheumatic complaints on 4 separate occasions by the CCQ telephone interview. The findings of the telephone interview were compared with a face-to-face interview and to rheumatologist examination, in 2 separate stages.The telephone applied CCQ had a sensitivity level of 88.6% and specificity of 70.0% when compared with the rheumatologist evaluation (κ = 0.576) (P0.001). A lower prevalence of rheumatic complaints was found in the summer months (17.7%) than in winter months (26.2%, P0.01). Prevalence was related to country of origin (0.008P0.03) (P range in separate surveys) and increasing age (P0.001) and was higher in women than in men (0.003P0.043). Body sites most affected were the lower back (63%) and the knees (47%). Medically related unemployment was more common in those with rheumatic complaints (7.9%) than in those without such complaints (2.9%, P0.01). Among those with rheumatic ailments, 12.7% had a related discapacity recognized by the Israeli National Insurance Institute.The telephone applied CCQ was reliable in screening for rheumatic complaints. Rates for rheumatic complaints in Israel were similar to those in some other countries. Rheumatic complaints were common, age- and gender-related, associated with work discapacity, and with country of origin. This is the first longitudinal prevalence survey of rheumatic complaints in Israel.

To assess the effect of the timing of vaccination in relation to administration of infliximab on the efficacy and safety of influenza vaccine in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS).The study population comprised 38 patients treated with infliximab at a mean dosage of 3 mg/kg (20 RA patients; 18 AS patients; 23 RA controls (treated with disease modifying antirheumatic drugs other than anti-tumor necrosis factor-alpha; and 17 healthy controls). Split-virion inactivated vaccine containing 15 mug hemagglutinin/dose of each of A/New Caledionan/20/1999 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004 (M) was used. Patients treated with infliximab were divided into 2 groups: 22 were vaccinated on the day of administration of infliximab, while 16 received the vaccine 3 weeks after infliximab. Baseline and 4- to 6-week clinical assessment of disease activity included erythrocyte sedimentation rate and C-reactive protein for all patients, the 28-joint disease-activity score for RA patients, and Bath Ankylosing Spondylitis Disease Activity Index for AS patients. Hemagglutination inhibition (HI) antibodies were tested by a standard World Health Organization procedure. Response was defined asor=4-fold rise in HI antibodies 4 to 6 weeks after vaccination, or seroconversion in patients with a nonprotective baseline level of antibodies (1/40). Geometric mean titers (GMT) were calculated to assess the immunity of the whole group.At baseline, RA patients and controls had similar occurrence of protective levels of HI antibodies and GMT, while AS patients had lower levels reflecting lower rates of previous vaccination. Four weeks after vaccination, a significant and similar increase in GMT for each antigen was observed in all groups (P0.004) except in the RA-infliximab group, vaccinated 3 weeks after administration of infliximab, in whom the increase in GMT was not significant for H1N1 (P = 0.12) and H3 (P = 0.06). AS patients demonstrated an increase in GMT, independently of the time of vaccination. The percentage of responders was similar in all groups. The response was not affected by variables such as age, gender, methotrexate, or prednisone use. Parameters of disease activity remained unchanged. No adverse effects other than injection site pain were recorded.Influenza virus vaccine generated a good humoral response in RA and AS patients treated with infliximab.

Background: Statins (3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors) exert favorable effects on lipopro- tein metabolism, but appeared to possess anti-inflammatory properties among others, as suggested by their ability to in- hibit collagen-induced arthritis in mice. Their activity in fibroblast-like synovial cells (FLS) has not yet been studied. Objectives: To evaluate the effect of varying doses of simvastatin on apoptosis of FLS. Methods: Synovial tissue, obtained during total knee replacement due to osteoarthritis, was cut into small pieces and cul- tured in Petri dishes with test materials, as previously described. FLS were incubated for 48 hours with 1 μmol/ml, 5 μmol/ml, 15 μmol/ml and 50 μmol/ml of simvastatin. Following incubation, apoptosis was analyzed by two-dimensional flow cytometry (FACS) using annexin V/PI staining according to the manufacturer's instructions. Results: Different concentrations of simvastatin induced apoptosis of FLS. The level proportion of apoptotic cells of rest- ing or activated with lipopolysaccharide (LPS; 3 μg/ml) FLS, not treated with simvastatin, was 21%. At 48 hours, the rate of apoptosis of activated fibroblasts, incubated with 1 μmol/ml, 5 μmol/ml, 15 and 50 μmol/ml was 22%, 32%, 48% and 41% respectively. Synovial cell viability evaluated by tetrazolium salt XXT was unaffected by the simvastatin concentra- tion used. Conclusion: Varying concentrations of simvastatin induce apoptosis of activated fibroblast-like synoviocytes, suggesting another possible mechanism of anti-inflammatory effects of statins in inflammatory conditions.

The duration of humoral immunity in patients treated with immunosuppressive drugs is poorly defined. The objective of the study was to investigate the effect of infliximab on the levels of antiviral antibodies against poliomyelitis, rubella and measles in rheumatoid arthritis (RA) patients. Fifty-two consecutive RA patients being treated with 3 mg/kg infliximab were prospectively studied. The antiviral antibody profiles for measles, rubella and three serotypes of poliomyelitis were tested on the day of the first infusion of infliximab and 6 months later. The study group comprised 36 women and 16 men (mean age 54 years, range 33-81) with a mean disease duration of 15 +/- 9 years. Forty-two (81%) patients were being treated with methotrexate and 22 (42%) were receiving prednisone. All patients had baseline protective levels of antibodies against measles and the three strains of polio, while 48 (92%) patients had protective antibodies against rubella. No significant change in the levels of antiviral antibodies was observed after 6 months of treatment with infliximab: from 3.67 at baseline to 3.87 IU/ml for measles, 169.50-197.0 IU/ml for rubella. No change was noticed for the geometric mean concentrations of antibodies against strains of poliomyelitis: 366-478 IU/ml for the Mahoney polio strain, 906-845 IU/ml for the MEF strain and 175-196 IU/ml for the Sauket strain. Patients with longstanding RA conserve long-term immunity to common viruses despite the use of immunosuppressive drugs. Levels of antiviral antibodies against measles, rubella and polio remain stable under treatment with infliximab.

Objectives: Tumor necrosis factor alpha (TNF- ) therapy has been implicated in the development of autoim- mune diseases. Our aim was to describe three patients with spondyloarthropathies who responded to infliximab, a chi- meric monoclonal antibody specific for TNF- , but developed new symptoms of spondyloarthropathies. In parallel, a re- view of the literature on psoriasis induced by TNF- 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 Crohn's 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 in- fliximab developed peripheral arthritis. A review of the literature revealed 63 cases of psoriasis induced by TNF- block- ers (33 on Infliximab, 16 on Etanercept and 14 on Adalimumab). The underlying diseases were variable, including all the spectrum of conditions for which TNF- 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  blockers, the psoriasis improving in a majority of 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.

Earlier we showed the generation of tolerizing human monocyte-derived DC following interaction with iC3b-opsonized apoptotic cells. In this study we examine the generation of DC with our previously described tolerogenic phenotype in patients with the systemic autoimmune disease systemic lupus erythematosus (SLE). Monocyte-derived DC were generated in 71 SLE patients, characterized, and then tested for clearance of iC3b-opsonized 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanineperchlorate-stained apoptotic cells using flow cytometry, and for autologous T-cell activation using autologous mixed lymphocyte reaction (AMLR), at the same time as controls. Compared with healthy, age- and gender-matched controls, SLE patients showed upregulation of MHC class II, with a mean expression of 130.5%+/-36.8% (p0.007); CD86 in immature DC from SLE patients, generated in autologous human or control plasma, were also upregulated, with mean expression 106.6%+/-18.0% (p0.03). A significant (20%) reduction in iC3b-apoptotic cell uptake, together with increased autologous mixed lymphocyte reaction, was seen in 75% of SLE patients. Mean 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanineperchlorate-stained apoptotic cell acquisition was 70.0%+/-24% (p0.0001) compared with healthy controls. Altered generation of a tolerizing DC phenotype was seen in at least one third of SLE patients following interaction with iC3b-opsonized apoptotic cells. These results suggest that a substantial portion of SLE patients fail to generate DC with a tolerizing phenotype.

Endothelial progenitor cells (EPCs) are a population of bone marrow derived cells which have been attributed with the ability to migrate into areas of tissue ischemia and to posses reparative qualities. EPCs have been shown to be decreased in level and function in various inflammatory disorders. Psoriasis and psoriatic arthritis are associated with an increase in cardiovascular morbidity. The aim of the study was to investigate the number of EPCs among patients suffering from psoriasis and psoriatic arthritis. Patients suffering from active psoriasis and psoriatic arthritis were recruited as well as healthy controls. Disease activity was assessed with the DAS-28, BASDAI and PASI scores. Peripheral blood mononuclear cells were isolated and EPC numbers evaluated by FACS analysis using the CD34/133 and CD34/KDR. No significant difference was found between numbers of EPCs between healthy controls, patients with psoriasis and psoriatic arthritis. A significant correlation was found between levels of VGEF and the BASDAI score. The results of the current study do not support a significant role for EPCs in the pathogenesis of psoriasis and psoriatic arthritis.

Selective targeting of cells engaged in pathological activities is a major challenge for medical research. We generated monoclonal antibodies (mAbs) that exclusively bind, at concentrations ranging from 2 to 100 microg/ml, to a modified CD44 variant (designated CD44vRA) expressed on synovial fluid cells from joints of rheumatoid arthritis (RA) patients. These mAbs cross-reacted with keratinocytes expressing wild type CD44vRA (CD44v3-v10) only at a relatively high concentration (200 microg/ml). Sequence analysis of CD44vRA cDNA revealed, in 33 out of 43 RA and psoriatic arthritis patients, an extra intron-derived trinucleotide, CAG, which allows translation of an extra alanine. This insertion imposes a configurational change on the cell surface CD44 of RA synovial fluid cells, creating an immunogenic epitope and potentiating the ability to produce disease-specific antibodies. Indeed, the anti-CD44vRA mAbs (designated F8:33) were able to induce apoptosis in synovial fluid cells from RA patients, but not in peripheral blood leukocytes from the same patients, in keratinocytes from normal donors or in synovial fluid cells from osteoarthritis patients. Furthermore, injection of anti-CD44vRA mAbs reduced joint inflammation in DBA/1 mice with collagen-induced arthritis. These findings show that anti-CD44vRA mAbs are both bioactive and RA-specific.

Objective.To estimate the longterm humoral response of an antipneumococcal polysaccharide vaccine (PPSV23) in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), or inflammatory bowel disease (IBD)-associated spondyloarthropathy (SpA), and the effect of demographic and clinical factors and treatment on the longterm efficacy of the vaccine.Methods.A total of 145 consecutive patients treated with biologics [tumor necrosis factor-α (TNF-α) or interleukin 6 (IL-6) receptor inhibitors] or methotrexate (MTX) participated in this study. Fifteen were excluded because of absent information regarding their vaccination status (n = 9) or because of technical problems in obtaining their serum sample (n = 6). They were diagnosed with RA (n = 63, 48.5%), PsA (n = 29, 22.3%), AS (n = 28, 21.5%), or IBD-associated SpA (n = 3, 2.3%). Their mean age was 54.6 years, and 61.5% were women. Data were collected on the timing of vaccination, demographic and clinical characteristics, and treatment, and patients’ serum antipneumococcal antibody levels were tested.Results.Two-thirds of the patients (67.7%) had received PPSV23 45 months (mean) earlier. Treatment included TNF-α inhibitors (73.9%), IL-6 receptor inhibitors (13.1%), or MTX without a biological treatment (13%). The uptake of vaccination was significantly higher in the older population (> 65 yrs). Vaccinated patients had significantly higher antibody levels compared with vaccine-naive patients. The antibody levels had been preserved after 10 years. MTX use, but not biologics, was associated with significantly lower antibody levels.Conclusion.The longterm efficacy of the PPSV23 vaccination seems to be preserved among patients with RA, PsA, AS, and IBD-associated SpA for at least 10 years. Efficacy is slightly impaired by MTX, but it is not affected by biologics. These findings suggest that revaccination after 5 years might not be needed for all, and testing the antibody titers should be considered to identify those who may benefit from revaccination.

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.

Objective: Monitoring of immune responses is essential in the care of immunosuppressed individuals, including rheumatic patients. Evaluation of cellular immunity is essential for confirming virus-specific effector cell functions, but it is poorly standardized, and suffers from technical limitations and inaccurate results. There is, therefore, a need for reliable techniques for assessing cell-mediated immunity. In this study we compared the cell-mediated immunity response to influenza vaccine between a population of rheumatoid arthritis (RA) patients and healthy subjects by three methods. Methods: Trivalent influenza subunit vaccine was administered to 18 RA patients who were taking disease-modifying antirheumatic drugs and to 18 healthy controls. Peripheral blood mononuclear cells (PBMCs) and sera were obtained immediately before and ~28 days after vaccination. Cell-mediated immunity responses to vaccination were evaluated by (1) flow cytometric analysis of IL-2/IFN-γ production in activated CD4/CD8 T-cells, (2) enzyme-linked immunosorbent assay for the analysis of IFN-γ secretion, and (3) Granzyme B activity assay. Humoral response was evaluated by the hemagglutination inhibition assay. Results: Vaccination induced a significant increase in PBMC IFN-γ secretion and Granzyme B activity in the RA patients. Granzyme B activity also significantly increased in the controls, but there was no change in the levels of secreted IFN-γ. No group differences in the frequencies of IFN-γ/IL-2-producing activated CD4/CD8 T-cells were observed by flow cytometry. The geometric mean of hemagglutination inhibition antibody titers increased significantly for the H1N1/H3N2 influenza strains in both groups. Conclusions: Granzyme B activity assay was the only method to detect a significant cell-mediated immunity response in both groups while significant increase in IFN-γ secretion was demonstrated only in RA patients. Flow cytometric analysis failed to show IL-2 and IFN-γ production in both groups. Currently available methods for measuring cellular responsiveness to influenza vaccination are inconsistent and limited in their ability to reflect acquired cellular immunity.

Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality, which may be attenuated by anti-inflammatory treatment. Endothelial progenitor cells (EPCs) have the ability to differentiate into mature endothelium and have a potentially reparative role protecting against ischemia and atherosclerosis.To investigate the effect of treatment with infliximab on the number and functional capacity of endothelial progenitor cells (EPCs) in patients with RA, as a possible mechanism for reducing cardiovascular morbidity in this disorder.Active seropositive RA patients (N = 14) considered candidates for starting infliximab treatment, were recruited. Assessment, based on DAS-28, was performed before treatment and 14 days later. Peripheral blood mononuclear cells were isolated and EPC numbers evaluated by the colony-forming unit (CFU) method. Endothelial phenotyping of CFU was performed by immunofluorescence employing antibodies to Tie-2 VEGF-receptor 2, and CD31. EPC Functional properties were evaluated by fibronectin adherance.A significant 33.4% increase (p0.001) in EPC levels was observed after infliximab. A 60% increase was noted in the EPC differentiation scale, (p0.002) while a 37.6% increase was observed in mean EPC adhesion (p0.001). These changes were associated with a 17.5% decrease in the DAS-28 (p0.0001). A significant correlation was observed between the clinical response, reflected by changes in DAS-28 and the degree of increase in EPC CFUs.A single dose of infliximab improved the number and functional properties of EPCs, in parallel with an early clinical effect, suggesting a possible mechanism by which anti-inflammatory treatment may reduce cardiovascular risk in RA patients.

Objectives To report 4 cases of propythiouracil (PTU)-induced lupus or vasculitis and to review the literature on that subject. Methods We describe the clinical presentation, course, and outcome of 4 patients and review the medical literature registered in the Medline PubMed database from 1966 to 2004 by using the keywords: Graves, thyrotoxicosis, propylthiouracil, lupus, vasculitis, arthritis, rash, ANA, and ANCA. Cases were classified into drug-induced lupus (DIL) or vasculitis using accepted definitions and evaluated with emphasis on gender, age, origin, duration of treatment, delay in diagnosis, clinical and serological features, and outcome. Results We described our 4 patients and analyzed 42 well-documented cases of DIL- and PTU-induced vasculitis (30 had vasculitis and 12 fulfilled the classification criteria of DIL). Patients with vasculitis were significantly older (mean 43 versus 22 years) and had a longer duration of treatment in comparison with DIL (35 versus 24 weeks). Musculoskeletal symptoms were prominent in DIL, while renal and pulmonary involvement was found in a significantly higher proportion of PTU-induced vasculitis. ANA, anti-DNA, and anti-histone were predominantly found in DIL, while p-ANCA was found in a similar proportion of patients in both groups. c-ANCA was detected only in patients with vasculitis. All patients with DIL completely recovered (most after stopping PTU), while about 50% of PTU-induced vasculitis needed steroids or immunosuppressive drugs, including cyclophosphamide and plasmapheresis. Conclusions Most of the cases of PTU-induced autoimmune phenomena are due to vasculitis. Despite the common presence of p-ANCA in both DIL- and PTU-induced vasculitis, substantial differences in demographic, clinical, and outcome features of these entities allow an accurate diagnosis and consequent management.

The CNS manifestations of the antiphospholipid syndrome (APS) can mimic multiple sclerosis both clinically and radiologically.To compare evoked potential studies in APS patients and patients with multiple sclerosis with similar neurological disability.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.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, p0.001). 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)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.

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.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.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.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.

Objective The purpose of this open pilot study was to assess possible mechanisms of the effects of leflunomide by studying the influence of the drug on the serum levels of MMP-1, MMP-3, IL-10, IL-6 and their possible correlation with clinical disease parameters. Patients and methods Thirty patients with long standing active rheumatoid arthritis were enrolled in this study. All patients failed at least 5 DMARDs in the past and were on stable treatment for at least 3 months before starting the protocol. The patients received a loading dose of 100 mg for 3 days followed by 20 mg/day thereafter and followed up monthly for 6 months. Disease activity was assessed at baseline, 2 weeks, and every month of therapy thereafter using the following variables: tender joint count, swollen joint count, morning stiffness duration, pain, tiredness, physician's and patient's global assessment, using VAS, ESR and CRP. Clinical effects of the treatment regimen were calculated using the American College of Rheumatology (ACR) criteria for clinical response. Adverse events were recorded. Serum levels of MMP-1, MMP-3, IL-10 and IL-6 were measured before and 3 months after starting the protocol. Results Except for tiredness, a statistically significant improvement in all clinical and laboratory parameters of disease activity was reached after 3 months. At this time point the ACR-20 response rate was 46.2%. The levels of MMP-1, MMP-3, IL-6 and IL-10 decreased significantly after 3 months. A statistically significant correlation between serum levels of MMP-1, IL-10 and IL-6 and clinical and laboratory parameters was also shown. After 6 months, 16 out of 30 patients withdrew from the study [adverse events (35.4%), lack of efficacy (9.7%), and low compliance (6.4%)]. Conclusions Leflunomide was clinically efficacious in this group of long standing resistant RA in an open study “real life” design. These results comply with those reported in previous clinical trials. Serum MMP-1, MMP-3, IL-10 and IL-6 levels decreased significantly. Despite high withdrawal rate, no serious adverse effects were recorded.

Objective.The longterm use of tumor necrosis factor (TNF)-α blockers is limited by the formation of neutralizing antibodies. To the best of our knowledge, immunogenicity in psoriatic arthritis (PsA) has not been investigated in depth. Our objective was to evaluate the prevalence and significance of TNF-α blocker immunogenicity in PsA.Methods.Consecutive patients with PsA treated with either infliximab (IFX), adalimumab (ADA), or etanercept (ETN) > 3 months participated in our cross-sectional study. Their demographic and clinical characteristics, skin and joint disease activity, and records of use of methotrexate (MTX) and other medications were collected. Drug levels (ELISA) and antidrug antibodies (ADAb; Bridging ELISA) were evaluated before the next injection or infusion.Results.A total of 93 patients with PsA were recruited (48 receiving ADA, 24 IFX, and 21 ETN), with a mean age of 53 years (range 21–83 yrs), composed of 53% women. One-fourth of the patients were concomitantly treated with MTX. Altogether, 77% of the patients demonstrated therapeutic drug levels. High levels of ADAb were found in 29% of patients taking ADA, 21% taking IFX, and 0% taking ETN. ADAb significantly correlated with lower drug levels, higher 28-joint Disease Activity Scores, and higher global assessments. MTX use correlated significantly with a lower prevalence of ADAb.Conclusion.Significant levels of ADAb were present in up to 29% of patients with PsA treated with ADA or IFX. ADAb clearly correlated with low therapeutic drug levels and higher disease activity variables. The use of MTX significantly decreased ADAb prevalence, and its use should be strongly considered in combination with TNF-α blocker antibodies in patients with PsA.

Therapy with TNFa 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.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.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.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.

This article challenges the dominant ‘victimizing’ overtones offering a balanced view of the love-hate interaction between politics and media in Israel. The political institution, and politicians in particular, are not helpless 'victims' up against the terrible media. The ongoing broadcast regulation that results in a three-stage process – maturation, implementation, negotiation – may characterize the relations between the two branches of the Israeli democracy. In the stage of maturation, possibly for months and even years, the political and economic circumstances enable the adoption of a medium innovation. In the implementation stage, the actual constaints are revealed, as expected, some of which are predictable and others unforeseen. In the final phase, the stage of negotiation, in light of the aforementioned gaps, bargain is held between the franchisers and the government, usually at the initiative of the former. These relations are analogous with a pendulum swinging between the authoritarian approach,...

The purpose of this open pilot study was to assess prospectively the effect of infliximab on extraintestinal manifestations in patients with active Crohn's disease refractory to conventional treatment.Twenty-two consecutive patients with Crohn's disease and one with ulcerative colitis presenting at least one of the known extraintestinal manifestations of Crohn's disease participated in the study. All the patients had Crohn's disease activity index (CAI) scores above 2. Each patient received an intravenous infusion of infliximab at a dosage of 5 mg/kg. A thorough questionnaire was used reviewing the extraintestinal manifestations of Crohn's disease such as erythema nodosum, pyoderma gangrenosum, eye lesions, arthritis or arthralgia, sacroiliitis or inflammatory back pain, hepatic disease, hematologic manifestations (megaloblastic, iron deficiency or hemolytic anemia, thrombocytosis), thrombosis, and nephrolithiasis. Musculoskeletal complaints were evaluated using the parameters intensity of pain, duration of morning stiffness (in minutes), presence of inflammatory back pain, Schober's test of the lumbar region, chest expansion, and distance from occiput to wall. The clinical assessment was performed on the day of the infusion and 2 weeks later.Eleven out of 23 patients had arthralgia of inflammatory nature, three others had evidence of active synovitis on physical examination, and 11 reported inflammatory back pain. Four patients suffered from protracted pyoderma gangrenosum; three had resistant aphthous stomatitis. Eleven patients had more than one extraintestinal manifestation. All four with pyoderma gangrenosum demonstrated significant improvement of their ulcers after one course of infliximab, with complete resolution of the skin lesions in three of them after repeated infusions of infliximab. Aphthous stomatitis completely responded in all patients after a single infusion. Seven out of 11 patients with arthralgia and seven out of 11 with inflammatory back pain/sacroiliitis experienced benefit after treatment with infliximab and reported at least partial clinical improvement in duration of morning stiffness, tender joint count, and visual analogue scale for pain. Only one of three patients with frank arthritis demonstrated clear improvement, and two others failed to respond to infliximab treatment.These preliminary results are encouraging and suggest a promising role of infliximab in the treatment of extraintestinal symptoms of Crohn's disease.

Somatostatin is a neuropeptide with modulatory effects on the immune system and the function of synovial cells; it has antiangiogenic and antiproliferative properties. This study aimed to evaluate the clinical, histological, and articular tissue cytokine mRNA response to somostatin treatment in rat adjuvant-induced arthritis (AIA).Adjuvant-induced arthritis was induced in a total of 68 Lewis rats by immunization with complete Freund's adjuvant. Twenty-four rats were treated with a long-acting somostatin analogue 14 days after disease induction. Twenty-four untreated rats served as controls. The severity of arthritis was scored weekly for 42 days. In a second experiment, 20 rats (ten treated, ten controls) were killed 21 days after treatment for assessment of joint histopathology and articular tissue cytokine mRNA expression.Somatostatin analogue treatment significantly reduced histological scores of early inflammatory changes and increased articular tissue mRNA expression of interleukin-1 beta (IL-1beta). A trend toward improvement in physical scores of joint inflammation was seen in the treated group. Late destructive changes were not significantly different.Treatment with a somostatin analogue attenuated early inflammatory changes in AIA joints and increased mRNA expression of IL-1beta in the articular tissues of rats with ongoing arthritis. Improvement in the physical findings of joint inflammation was mild.

This study was designed to investigate the distribution of human leukocyte antigen (HLA) classes I and II in a group of Israeli Jewish patients with psoriatic arthritis (PsA) and identify HLA markers related to disease manifestation in PsA.Human leukocyte antigens class I and class II (both serologically and from oligotyping) were tested in a group of 50 consecutive patients with PsA, 32 with skin psoriasis (PSO), and 255 healthy persons. Data on age, gender, disease duration, and pattern of rheumatological manifestations-oligoarthritis, polyarthritis, spinal involvement, involvement of distal interphalangeal joints (DIPs), and enthesitis-were registered.Human leukocyte antigens A3, B13, and B38 alleles were found to be significantly prevalent in PsA compared with PSO patients and healthy controls. HLA-B27 was found in only two out of 50 patients with PsA. Patients with PSO and PsA had significantly increased incidence of HLA-DRB0101 and -DRB0301, while the frequency of HLA-DRB0403 was significantly higher among patients with PsA of Ashkenazi origin. We found a statistically significant association between DIP involvement and the presence of HLA-A26 and -B38, while HLA-DRB0301 was related to spinal involvement.Psoriatic arthritis in Israeli patients seems to be associated with the presence of HLA-A3, -B13, -B38, -DRB0101, and -DRB0301. HLA-B27 was not a marker of PsA in this cohort of patients, including patients with psoriatic spondyloarthropathy.

Although 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). Levels 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. The 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 (

Although low-dose aspirin is used by many elderly patients, monitoring of renal function is currently not recommended. We recently reported transient retention of uric acid and creatinine caused by aspirin in doses of 75 to 325 mg/d. We therefore evaluated the renal effects of aspirin (100 mg/d), including post-treatment effects.We studied 83 stable geriatric patients in long-term care (aged 56 to 98 years) who were treated with low-dose aspirin (100 mg/d) for 2 weeks and 40 control patients. Other medications and diet were kept constant. Biochemical monitoring including blood samples and 24-hour urinary collections for creatinine and uric acid at baseline and weekly for a total of 5 weeks.After 2 weeks on aspirin, urinary excretion of creatinine decreased in 60 (72%) and excretion of uric acid decreased in 54 (65%) of the 83 patients, and their mean clearances decreased; during the same period, serum blood urea nitrogen, creatinine, and uric acid levels increased (P0.05 for all). Deterioration from baseline levels was significantly greater (and more prevalent) in the aspirin-treated group than in the 40 control patients (P = 0.001 to 0.09). After withdrawal of aspirin these parameters improved. However, 3 weeks after stopping aspirin, 48% (35 of the 73 in whom this measurement was available) had a persistent decline in creatinine clearance from baseline, as compared with only 8% (3/36) controls (P0.001).Short-term low-dose aspirin treatment may affect renal function in elderly patients. These effects persist 3 weeks after cessation of the drug in some of these patients.

A previouslydiagnosed systemic lupus erythematosuspatient presented with arthralgia, skin rash and muscular weakness. When treated with high-dose corticosteroids and methotrexate she improved, except for a persistent lesion in the hand which evolved into a profound ulcer, along with tender subcutaneous nodules in the calf. A skin biopsy disclosed necrotizing vasculitis with giant cell granuloma revealing acid fast positive bacteria on ziels nilsen staining. A chest X-ray disclosed miliary tuberculosis (TB). The patient was diagnosed as miliary TB with prominent cutaneous involvement and treated with four anti-tuberculous drugs with slow resolution of her systemic, pulmonary and skin signs.