Rheumatoid Arthritis: Caspi D

Elkayam O, Ablin J, Caspi D. · Department of Rheumatology, Tel Aviv Medical Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel. · Autoimmun Rev. · Pubmed #17412304 No free full text.

Abstract: Vaccination against streptococcus pneumonia is currently recommended for patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Safety and efficacy issues of vaccination in patients suffering from rheumatic diseases are still unresolved. This review summarizes the studies performed on the safety and immunogenicity of pneumococcal vaccination in patients with RA and SLE, with special emphasis on the effect of immunosuppressive drugs on the efficacy of the vaccine. Several trials have shown that the vaccine does not induce clinical exacerbation of RA and that it does induce an adequate humoral response, albeit one lower than that in healthy controls.

Elkayam O, Caspi D. · No affiliation provided · Clin Exp Rheumatol. · Pubmed #15301255 No free full text.

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Silverman MH, Strand V, Markovits D, Nahir M, Reitblat T, Molad Y, Rosner I, Rozenbaum M, Mader R, Adawi M, Caspi D, Tishler M, Langevitz P, Rubinow A, Friedman J, Green L, Tanay A, Ochaion A, Cohen S, Kerns WD, Cohn I, Fishman-Furman S, Farbstein M, Yehuda SB, Fishman P. · Can-Fite BioPharma Ltd, Petach Tikva, Israel. · J Rheumatol. · Pubmed #18050382 No free full text.

Abstract: OBJECTIVE: Adenosine exerts antiinflammatory effects via activation of the A3 adenosine receptor (A3AR), a Gi protein-associated cell-surface receptor, overexpressed in synovial tissue and peripheral blood mononuclear cells (PBMC) in patients with active rheumatoid arthritis (RA). CF101 is a highly specific orally bioavailable A3AR agonist. METHODS: This was a multicenter study, blinded to dose, designed to assess the clinical activity and safety of CF101 in active RA. Seventy-four patients were randomized to receive 0.1, 1.0, or 4.0 mg CF101 bid for 12 weeks. The primary efficacy endpoint was American College of Rheumatology 20% response (ACR20) at Week 12. A3AR expression levels were analyzed in PBMC from 18 patients. RESULTS:. Maximal responses were observed with 1.0 mg bid, lower at 0.1 and 4.0 mg bid. At 12 weeks, 55.6%, 33.3%, and 11.5% of the patients receiving 1.0 mg CF101 achieved ACR20%, 50%, and 70% responses, respectively. CF101 was generally well tolerated, with mild headache (4.1%), nausea (2.7%), and rash (2.7%) being the most common treatment-related adverse events. Statistically significant correlations between A3AR overexpression at baseline and ACR50 and ACR70 responses were observed. CONCLUSION: CF101 administered bid for 12 weeks resulted in improvement in signs and symptoms of RA that did not achieve statistical significance, and was safe and well tolerated. The expression level of A3AR was directly correlated with patient responses to CF101, suggesting its utilization as a biomarker for the pharmacodynamic and therapeutic effects of this novel agent. These findings require confirmation in a double-blind randomized placebo-controlled trial, currently under way.

Oren S, Mandelboim M, Braun-Moscovici Y, Paran D, Ablin J, Litinsky I, Comaneshter D, Levartovsky D, Mendelson E, Azar R, Wigler I, Balbir-Gurman A, Caspi D, Elkayam O. · Department of Rheumatology, Tel Aviv Sourasky Medical Centre, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 64239, Israel. · Ann Rheum Dis. · Pubmed #17981914 No free full text.

Abstract: 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.

Litinsky I, Paran D, Levartovsky D, Wigler I, Kaufman I, Yaron I, Yaron M, Caspi D, Elkayam O. · Department of Rheumatology, Sourasky Medical Center, and Sackler, Faculty of Medicine, University of Tel Aviv, 6 Weizman Street, Tel Aviv 64239, Israel. · Cytokine. · Pubmed #16487722 No free full text.

Abstract: 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.

Elkayam O, Yaron M, Caspi D. · Department of Rheumatology, Tel Aviv Sourasky Medical Centre and the Sackler Faculty of Medicine, University of Tel Aviv, Israel. · Ann Rheum Dis. · Pubmed #12079904 links to  free full text

Abstract: BACKGROUND: Hepatitis B infection and vaccination against it have been implicated in the potential triggering or flare of some autoimmune diseases, including rheumatoid arthritis (RA). However, the safety of hepatitis B vaccination in patients with pre-existing RA is not known. OBJECTIVES: To assess the safety and antibody response of immunisation with a recombinant DNA hepatitis B vaccine in patients with RA. PATIENTS AND METHODS: The study comprised 44 patients with RA, of whom 22 received three doses (the second and third dose being given after one and six months) of a recombinant DNA hepatitis B vaccine (study group) and 22 did not receive the vaccine (control group). Both groups had comparable proportions of women and similar mean age (51 years). Clinical assessment before and two and seven months after the first immunisation included evaluation of daytime pain with a 10 cm visual analogue scale, duration of morning stiffness, and number of tender and swollen joints. Erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) were measured at each visit. Antibodies to hepatitis B surface antigen (HBsAg) were determined by a commercial enzyme linked immunosorbent assay (ELISA) test kit. RESULTS: Hepatitis B vaccination was not associated with an appreciable deterioration in any clinical or laboratory measure of disease. The measures of disease activity of the patients and controls during the study period did not differ significantly: p=0.76 for daytime pain, p=0.1 for morning stiffness, p=0.24 and p=0.3 for tender and swollen joints respectively, p=0.08 for CRP, and p=0.12 for ESR. Fifteen of the 22 patients responded to vaccination, with an antibody level against HBsAg of 10 IU/l after seven months. Lack of response was associated with older age and higher scores of daytime pain. CONCLUSIONS: Hepatitis B vaccination is safe in RA and produces antibodies in 68% of the patients.

Kaufman I, Schwartz D, Caspi D, Paran D. · Department of Rheumatology, Tel Aviv Sourasky Medical Centre, Tel Aviv University, Tel Aviv, Israel. · Scand J Rheumatol. · Pubmed #18465457 No free full text.

Abstract: OBJECTIVE: To present a case of severe interstitial nephritis with proteinuria in primary Sjögren's syndrome (pSS) and review the literature regarding renal disease and its management in pSS, aiming to suggest recommendations for treatment. METHODS: A search of MEDLINE (PubMed) was performed for review articles and case reports using the MESH terms: Sjögren syndrome; renal disease; interstitial nephritis (IN); glomerulonephritis (GN). RESULTS: We describe a rare case of pSS presenting with hypokalaemic tetraparesis and proteinuria due to severe IN, successfully treated with high-dose steroids and azathioprine. Reviewing the literature, we identified 180 reported cases of renal involvement in pSS (selected based on the European criteria for pSS), 89 of which underwent renal biopsies revealing IN in 49 cases, GN in 33 samples, and both IN and GN in seven. Eighteen studies reported treatment experience of renal disease in 32 pSS cases. Seventeen patients were treated with corticosteroids and cyclophosphamide, and 15 patients received only steroids with improvement in the majority of cases. CONCLUSION: The present case, as well as the limited number of reports in the literature, suggest that renal involvement, including IN, in pSS may improve with immunosuppressive therapy. Further studies are required to determine indications for and dosages of immunosuppressive treatment in patients with renal involvement of pSS.

Eshkar Sebban L, Ronen D, Levartovsky D, Elkayam O, Caspi D, Aamar S, Amital H, Rubinow A, Golan I, Naor D, Zick Y, Golan I. · Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel. · J Immunol. · Pubmed #17617615 links to  free full text

Abstract: The synovial fluid (SF) cells of rheumatoid arthritis (RA) patients express a specific CD44 variant designated CD44vRA. Using a cellular model of this autoimmune disease, we show in this study that the mammalian lectin, galectin-8 (gal-8), is a novel high-affinity ligand of CD44vRA. By affinity chromatography, flow cytometry, and surface plasmon resonance, we demonstrate that gal-8 interacts with a high affinity (K(d), 6 x 10(-9) M) with CD44vRA. We further demonstrate that SF cells from RA patients express and secrete gal-8, to a concentration of 25-65 nM, well within the concentration of gal-8 required to induce apoptosis of SF cells. We further show that not all gal-8 remains freely soluble in the SF and at least part forms triple complexes with CD44 and fibrinogen that can be detected, after fibrinogen immunoprecipitation, with Abs against fibrinogen, gal-8 and CD44. These triple complexes may therefore increase the inflammatory reaction by sequestering the soluble gal-8, thereby reducing its ability to induce apoptosis in the inflammatory cells. Our findings not only shed light on the receptor-ligand relationships between CD44 and gal-8, but also underline the biological significance of these interactions, which may affect the extent of the autoimmune inflammatory response in the SF of RA patients.

Golan I, Nedvetzki S, Golan I, Eshkar-Sebban L, Levartovsky D, Elkayam O, Caspi D, Aamar S, Amital H, Rubinow A, Naor D. · The Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel. · J Autoimmun. · Pubmed #17383158 No free full text.

Abstract: 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.

Ablin JN, Boguslavski V, Aloush V, Elkayam O, Paran D, Caspi D, George J. · Department of Rheumatology, Tel-Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. · Life Sci. · Pubmed #16962143 No free full text.

Abstract: 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. OBJECTIVE: 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. METHODS: Patients: 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. RESULTS: A significant 33.4% increase (p < 0.001) in EPC levels was observed after infliximab. A 60% increase was noted in the EPC differentiation scale, (p < 0.002) while a 37.6% increase was observed in mean EPC adhesion (p < 0.001). These changes were associated with a 17.5% decrease in the DAS-28 (p < 0.0001). A significant correlation was observed between the clinical response, reflected by changes in DAS-28 and the degree of increase in EPC CFUs. CONCLUSION: 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.

Caspi D, Anouk M, Golan I, Paran D, Kaufman I, Wigler I, Levartovsky D, Litinsky I, Elkayam O. · Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, University of Tel Aviv, Tel Aviv 64239, Israel. · Arthritis Rheum. · Pubmed #16463412 links to  free full text

Abstract: OBJECTIVE: To assess the levels of anti-cyclic citrullinated peptide (anti-CCP) and IgA rheumatoid factor (IgA-RF) in synovial fluids of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and osteoarthritis (OA). METHODS: Knee effusions of 29 patients with RA (23 women, 6 men; mean +/- SD age 60 +/- 15 years), 20 with PsA (6 women, 14 men; mean age 51 +/- 12 years), and 19 with OA (9 women, 10 men; mean age 73 +/- 11.8 years) were aspirated, tested for white blood cell (WBC) counts, centrifuged, and stored at -20 degrees . Sera of 22, 11, and 12 of these patients with RA, PsA, and OA, respectively, were similarly stored. IgG anti-CCP and IgA-RF were detected by enzyme-linked immunosorbent assay. Erythrocyte sedimentation rate and C-reactive protein levels were used as measures of disease activity. RESULTS: Mean levels of synovial fluid anti-CCP and IgA-RF were significantly increased in RA joint effusions compared with PsA and OA (anti-CCP: 150 +/- 134, 34 +/- 29, and 24 +/- 26 units, respectively [P < 0.003]; IgA-RF: 76 +/- 77, 15.7 +/- 10, and 18 +/- 20 units, respectively). No significant difference was noted between OA and PsA. A significant correlation was found between synovial fluid anti-CCP and serum anti-CCP and IgA-RF. In patients with RA, a significant correlation was found between synovial fluid WBC counts and IgA-RF (P = 0.03) and serum IgA-RF (P = 0.008), but not between synovial fluid and serum anti-CCP levels. In RA patients, C-reactive protein correlated with serum IgA-RF. CONCLUSION: Anti-CCP and IgA-RF were significantly increased in synovial fluid of RA in comparison with PsA and OA patients.

Elkayam O, Burke M, Vardinon N, Zakut V, Yitzhak RB, Paran D, Levartovsky D, Litinsky I, Caspi D. · Department of Rheumatology, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, 6 Weizman Street, Tel Aviv University, Tel Aviv 64239, Israel. · Autoimmunity. · Pubmed #16040336 No free full text.

Abstract: PURPOSE: 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. 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.

Fomin I, Caspi D, Levy V, Varsano N, Shalev Y, Paran D, Levartovsky D, Litinsky I, Kaufman I, Wigler I, Mendelson E, Elkayam O. · Department of Rheumatology, Tel Aviv Medical Centre, 6, Weizman Street, Tel Aviv 64239, Israel. · Ann Rheum Dis. · Pubmed #16014674 links to  free full text

Abstract: 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.

Elkayam O, Caspi D, Reitblatt T, Charboneau D, Rubins JB. · Department of Rheumatology, Tel Aviv Sourasky Medical Center, Israel. · Semin Arthritis Rheum. · Pubmed #14978666 No free full text.

Abstract: OBJECTIVE: To assess the effect of anti-tumor necrosis factor (TNF) alpha therapies on the immunogenicity of pneumococcal vaccination in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). METHODS: A group of 16 consecutive patients (11 with RA and 5 with AS) treated either with infliximab or etanercept, and a control group of 17 age-matched RA patients treated with disease-modifying medications other than anti-TNF-alpha, received intradeltoid injection with 0.5 mL of pneumococcal vaccine. Pneumococcal polysaccharide (PPS)-specific IgG to 7 vaccine PPS (representing high- and low-prevalence serotypes) was measured by enzyme-linked immunosorbent assay in sera obtained before and 1 month after pneumococcal immunization. RESULTS: One month after vaccination, both groups had significant increases in the geometric mean concentration of capsule PPS-specific antibody and in the mean fold increase in antibody levels to all 7 serotypes, compared with prevaccination levels. However, compared with the control group, the TNF-alpha blockade-treated patients tended to have lower antibody increases for all the serotypes tested except serotype 14. In addition, lower proportions of TNF-alpha blockade-treated patients responded to pneumococcal vaccination compared with patients on other therapies. Similarly, more TNF-alpha blockade-treated patients were poor responders compared with patients not on anti-TNF-alpha treatment. CONCLUSION: Treatment of groups of patients with etanercept or infliximab does not impair their mean antibody responses to pneumococcal vaccination. However, a larger proportion of RA patients may not respond adequately to pneumococcal vaccination once on TNF-alpha blockade therapies. Consequently, pneumococcal vaccination before starting TNF-alpha blockade therapy is recommended.

Segal R, Baumoehl Y, Elkayam O, Levartovsky D, Litinsky I, Paran D, Wigler I, Habot B, Leibovitz A, Sela BA, Caspi D. · Department of Geriatrics, Shmuel-Harofeh Geriatric Medical Center, Baer Yaakov, Israel. · Rheumatol Int. · Pubmed #12720045 No free full text.

Abstract: OBJECTIVE: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). METHODS: 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. RESULTS: 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 (<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. CONCLUSIONS: The 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.

Nedvetzki S, Golan I, Assayag N, Gonen E, Caspi D, Gladnikoff M, Yayon A, Naor D. · The Lautenberg Center for General and Tumor Immunology, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel. · J Clin Invest. · Pubmed #12697740 links to  free full text

Abstract: Synovial fluid cells from joints of rheumatoid arthritis (RA) patients express a novel variant of CD44 (designated CD44vRA), encoding an extra trinucleotide (CAG) transcribed from intronic sequences flanking a variant exon. The CD44vRA mutant was detected in 23 out of 30 RA patients. CD44-negative Namalwa cells transfected with CD44vRA cDNA or with CD44v3-v10 (CD44vRA wild type) cDNA bound FGF-2 to an equal extent via their associated heparan sulfate chains. However, Namalwa cells, immobilizing FGF-2 via their cell surface CD44vRA, bound substantially more soluble FGF receptor-1 (FGFR-1) than did Namalwa cells immobilizing the same amount of FGF-2 via their cell surface CD44v3-v10. The former cells stimulated the proliferation of BaF-32 cells, bearing FGFR-1, more efficiently than did the latter cells. Finally, isolated primary synovial fluid cells from RA patients expressing CD44vRA bound more soluble FGFR-1 to their cell surface-associated FGF-2 than did corresponding synovial cells expressing CD44v3-v10 or synovial cells from osteoarthritis patients. The binding of soluble FGFR-1 to RA synovial cells could be specifically reduced by their preincubation with Ab's against the v3 exon product of CD44. Hence, FGF-2 attached to the heparan sulfate moiety expressed by the novel CD44 variant of RA synovium cells exhibits an augmented ability to stimulate FGFR-1-mediated activities. A similar mechanism may foster the destructive inflammatory cascade not only in RA, but also in other autoimmune diseases.

Elkayam O, Yaron I, Shirazi I, Judovitch R, Caspi D, Yaron M. · Department of Rheumatology, Tel Aviv Sourasky Medical Center, Israel. · Ann Rheum Dis. · Pubmed #12695157 links to  free full text

Abstract: BACKGROUND: Leflunomide is now an approved agent for the management of adult rheumatoid arthritis (RA). Its active metabolite A771726 inhibits de novo pyrimidine biosynthesis. Although considered to be an immunosuppressive agent, its mechanism of action remains obscure. OBJECTIVES: Evaluation of the leflunomide active metabolite A771726 (LEF) effect on interleukin 1beta (IL1beta), tumour necrosis factor (TNFalpha), nitric oxide (NO), and stromelysin (metalloproteinase-3 (MMP-3)) production by activated human synovial tissue in culture. METHODS: Synovial tissue was obtained during surgery from patients undergoing total knee replacement owing to RA or osteoarthritis (OA), cut into small pieces, and cultured in Petri dishes with test materials as previously described. IL1beta, TNFalpha, NO, and MMP-3 were measured in the culture media after 48 hours incubation with different doses of LEF by methods previously described. RESULTS: LEF (0.3, 3, and 9 micro g/ml) inhibited IL1beta production in the presence of lipopolysaccharide (LPS; 3 micro g/ml) in a dose dependent manner (p<0.01) at LEF 0.3 micro g/ml. TNFalpha production in the presence of IL1beta (1 ng/ml) was also inhibited in a dose dependent manner (p<0.05 at LEF 0.3 micro g/ml). NO and MMP-3 production in the presence of LPS (3 micro g/ml) was inhibited as well (p<0.01 at LEF 1 micro g/ml and at LEF 0.3 micro g/ml, respectively). Synovial cell viability evaluated by the tetrazolium salt XTT was unaffected by the LEF concentration used. There was no qualitative difference in the response of OA and RA synovial tissue. CONCLUSION: Leflunomide may modulate the rheumatoid articular process by inhibition of local production of IL1beta, TNFalpha, NO, and MMP-3.

Elkayam O, Hawkins PN, Lachmann H, Yaron M, Caspi D. · Department of Rheumatology, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel. · Arthritis Rheum. · Pubmed #12384913 links to  free full text

Abstract: We describe herein a patient with rheumatoid arthritis who developed proteinuria due to AA amyloidosis, in whom the inflammatory disease was rapidly and completely suppressed by treatment with infliximab. This response was accompanied by resolution of the proteinuria and stabilization of the amyloid deposits as seen on serial (123)I-labeled serum amyloid P scintigraphy.

Elkayam O, Paran D, Caspi D, Litinsky I, Yaron M, Charboneau D, Rubins JB. · Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. · Clin Infect Dis. · Pubmed #11740700 No free full text.

Abstract: Prevention of bacterial infection, which is a leading cause of morbidity in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), is a priority. However, the safety and immunogenicity of the pneumococcal vaccine in such patients remain controversial. We evaluated the currently available pneumococcal vaccine in patients with RA or SLE. Pneumococcal vaccination was not associated with an appreciable deterioration in any clinical or laboratory measure of disease activity in either group. One month after vaccination, patients in both groups had significant increases in geometric mean concentrations of pneumococcal polysaccharide-specific IgG to all 7 serotypes tested, as did control subjects. However, 14 (33.3%) of 42 patients with RA and 5 (20.8%) of 24 patients with SLE responded either to none or to only 1 of the 7 polysaccharides. Pneumococcal vaccination is generally safe and immunogenic in patients with RA or SLE, but a subset of patients may remain unprotected by the currently available vaccine.

Paran D, Elkayam O, Mayo A, Paran H, Amit M, Yaron M, Caspi D. · Tel-Aviv Sourasky Medical Centre, Tel-Aviv University, Israel. · Ann Rheum Dis. · Pubmed #11502617 links to  free full text

Abstract: OBJECTIVE: To evaluate the efficacy and safety of a long acting somatostatin analogue in a subset of patients with refractory rheumatoid arthritis (RA). METHODS: Ten patients with active, refractory RA, who had failed to respond to at least four disease modifying antirheumatic drugs (DMARDs), were treated with monthly intramuscular injections of 20 mg of a long acting preparation of octreotide (Sandostatin-LAR) for three months. They were evaluated every two weeks in an open label pilot study. The primary measure of clinical response was the American College of Rheumatology criteria for a 20% improvement in measures of disease activity (ACR 20). RESULTS: Eight patients completed the 14 week trial, while two patients received only one or two doses of the somatostatin analogue, but were eligible for evaluation. On an intention to treat basis 6/10 patients responded: four patients met the ACR 20 criteria at weeks 6-10, while two patients continued to improve with time, and met the ACR 50 and 70 criteria respectively, at week 14. On evaluation of the 10 patients as a group, a significant improvement (p<0.05) was noted in the mean visual analogue scales of pain, doctor's and patient's global assessment of disease activity, and in the mean number of swollen joints. Adverse effects were minor: transient bloating and loose stools, an urticarial rash (n=1), and a transient increase of liver enzymes (n=1). CONCLUSION: Treatment with a long acting somatostatin analogue led to significant clinical improvement in a subset of patients with active, refractory RA. The treatment was relatively safe and well tolerated. Further large, placebo controlled studies are required to evaluate this drug as a potential DMARD for patients with RA.

Caspi D, Flusser G, Farber I, Ribak J, Leibovitz A, Habot B, Yaron M, Segal R. · Departments of Rheumatology and Radiology, Tel Aviv (Souraski) Medical Center, Tel Aviv, Israel. · Semin Arthritis Rheum. · Pubmed #11303305 No free full text.

Abstract: OBJECTIVE: Osteoarthritis (OA) of the hand is common in elderly patients. The aim of this study was to characterize OA frequency, severity, and distribution and to trace interrelationships between these findings and the demographic, occupational, and medical data from elderly Jewish nonrheumatologic patients. METHODS: Study participants were 253 consecutive patients admitted to a geriatric center for a variety of nonrheumatic medical conditions. Excluded patients were those with rheumatoid arthritis; neurologic, orthopedic, or other conditions that would interfere with symmetric hand function; and mental or medical states that would interfere with history taking and radiographic studies. Patient occupations were graded as workload degree (on a scale of 1 to 3) and as the total occupational score (workload degree multiplied by the duration of each job). Clinical findings of Heberden nodes, Bouchard nodes, and malignment, graded on a scale of 0 to 3, were summed as the clinical OA score. Hand radiographs were independently read (modified Altman method), grading 5 parameters in each joint on a scale of 0 to 3, summed as a radiologic OA score. Statistical analyses included the Student t test, chi(2) test, ANOVA, Pearson correlation, and partial correlation coefficients. RESULTS: Among 253 elderly patients (171 women, 82 men; mean age, 79 years) OA was frequent (occurring in about 80% of patients), involving most severely the second and third distal interphalangeal, right first interphalangeal, and both first carpometacarpal joints. The prevalence of OA was similar in women and men, with higher scores in women, and reached significance only in the distal interphalangeal joints. Metacarpophalangeal joints were more involved in men. Age had a clear influence on OA scores. Ethnicity affected OA severity, with Ashkenazi Jews having significantly higher scores than Sepharadi Jews. Dominant hands had significantly higher global OA scores as well as isolated joint scores (except for the first carpometacarpal joint). Occupational load, housekeeping tasks, and the number of children did not influence the total or specific joint OA scores. Associated conditions such as obesity, diabetes, hypothyroidism, and chondro calcinosis were not associated with more pronounced OA. CONCLUSIONS: Hand OA was prevalent in our elderly cohort, and its severity was influenced by inherent traits such as age, female gender, ethnicity, and handedness. In contrast, acquired factors such as workload, number of children, and associated diseases did not appear to influence OA expression.

Caspi D, Elkayam O, Eisinger M, Vardinon N, Yaron M, Burke M. · Department of Rheumatology, Tel Aviv (Sourasky) Medical Center, Israel. · Rheumatol Int. · Pubmed #11269531 No free full text.

Abstract: The objective of this study was to evaluate the clinical significance of anti-nuclear antibodies (ANA) detected in the early stages of rheumatoid arthritis (RA), by a retrospective comparison of the clinical, laboratory, and therapeutic characteristics of patients with or without ANA. The files of 99 longstanding seropositive RA patients were reviewed. Data relating to demographics, medical history, family history, physical findings, extra-articular complications, laboratory tests, drugs [dosage, duration. efficacy, combinations, adverse effects (AEs)], intra-articular injections, and surgery were recorded. Patients with or without ANA at presentation of their disease were compared using chi-square and t-tests. Fifty-two ANA positive (group 1) and 47 ANA negative (group 2) patients were enrolled in the study. All were comparable in terms of their mean age, age at diagnosis, follow-up duration (approximately 10.5 years), and male:female (M:F) ratio. On admission, pain complaints were more pronounced in group 1 (P = 0.004 in the feet), but the physical findings did not differ. Deformities and nodules developed in similar numbers. Extra-articular complications were evenly distributed; vasculitis, however, was significantly more prevalent in ANA positive (10/52) than in ANA negative (2/47) patients. Thyroid disease was more common in group 2 (10/47 vs 3/52). Laboratory tests (presentation and maximal values) were similar, with the exception of higher anti-DNA (but within normal ranges) and gamma-globulin% in group 1. Group 1 used more drugs prior to diagnosis. Corticosteroids and disease-modifying anti-rheumatic drugs (DMARDs) were evenly used. Combination therapy, joint injections, and surgery were more prevalent in group 2. AEs to various DMARDs were more common in group 1. Although similar in many aspects, RA patients with ANA tend to present with more pain complaints, a higher risk of vasculitis and AEs relating to use of DMARDs, while those without ANA needed more aggressive therapeutic modalities.

Elkayam O, Yaron I, Shirazi I, Yaron M, Caspi D. · Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. · Clin Rheumatol. · Pubmed #11147755 No free full text.

Abstract: The purpose of this study was to evaluate the serum levels of hyaluronic acid (HA) in a group of patients with psoriatic arthritis (PsA), with special emphasis on the relationships between HA levels and clinical parameters of joint and skin activity. Thirty-four patients with PsA, 34 patients with rheumatoid arthritis (RA) and 49 healthy volunteers participated in the study. Assessment of joint disease in patients with PsA included duration of morning stiffness, number of tender and swollen joints, right and left grip, the presence of inflammatory back pain and Schober's test. The current severity of skin involvement was graded according to the Psoriasis Area Severity Index (PASI). Serum levels of HA were measured by a radiometric assay. The mean HA serum levels of patients with PsA and RA were significantly increased in comparison with healthy controls (107 +/- 39.6 microg/dl in patients with PsA, whereas in patients with RA it was 168 +/- 32.4 microg/dl and 36.7 +/- 5.5 microg/dl in healthy controls). A highly significant correlation was found between levels of HA and index of skin involvement, but no association was found between HA levels and clinical parameters of joint severity. We conclude that in this cohort of patients with PsA, HA levels clearly reflected psoriatic skin involvement although it did not correlate with joint disease.

Elkayam O, Paran D, Flusser G, Wigler I, Yaron M, Caspi D. · Department of Rheumatology, Sourasky Medical Center, Tel Aviv University, Israel. · Clin Exp Rheumatol. · Pubmed #10895375 No free full text.

Abstract: OBJECTIVE: To report 9 patients with rheumatic diseases referred to our observation due to presumed exacerbation of their rheumatic disease, subsequently diagnosed as stress insufficiency fractures, and to characterize the clinical profile of patients prone to this complication. METHODS: The medical history of the patients was reviewed with special emphasis on their rheumatic disease, its course, duration and management, their menopausal state, location and characteristics of the fracture, its presentation and the initial presumed diagnosis, the delay in diagnosis, imaging diagnostic tests performed and outcome. Three representative case reports are presented. RESULTS: All 9 patients were women, 8 of them aged 50 years old or more, 8 with rheumatoid arthritis and 1 with polymyalgia rheumatica. They were all treated with corticosteroids and had reduction in their bone mass density when evaluated. Three of the patients presented with subcapital fracture of the femur, 4 had fractures of metatarsal bones and 2 had fractures of the distal tibia. In only one patient was a stress fracture initially suspected. Diagnosis was delayed by a mean of 31 days. CONCLUSION: The diagnosis of stress fractures in patients with rheumatic diseases may often be delayed or missed, and thus improperly treated. Increased awareness of this entity is of importance for prompt diagnosis and correct management.