Rheumatoid Arthritis: Litinsky I

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.

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.

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.

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.