Arthritis & Rheumatism

doi: 10.1002/art.1780340521pmid: N/A

doi: 10.1002/art.1780340501pmid: N/A

Altman, R.; Alarcón, G.; Appelrouth, D.; Bloch, D.; Borenstein, D.; Brandt, K.; Brown, C.; Cooke, T. D.; Daniel, W.; Feldman, D.; Greenwald, R.; Hochberg, M.; Howell, D.; Ike, R.; Kapila, P.; Kaplan, D.; Koopman, W.;

Boyd, R. D.; Walker, E. R.; Wu, D. D.; Lukoschek, M.; Burr, D. B.; Radin, E. L.

doi: 10.1002/art.1780340503pmid: 2025305

We sought to determine whether synovial leukocytic inflammation is a primary event in mechanically induced osteoarthrosis. Repetitive impulse loading (50 ms duration at 60 Hz for 40 minutes each day) was applied to the right hindlimbs of 24 New Zealand white rabbits for 3, 6, or 9 weeks. The synovial membrane from the medial suprapatellar area was examined qualitatively using transmission electron microscopy and quantitatively using light microscopic morphometry. The results indicate that synovial inflammation is not a primary event in this mechanically induced osteoarthrosis, but synovial hyperplasia occurs prior to histologically evident cartilage destruction at 6–9 weeks.

Reiter, Christian; Kakavand, Bahram; Rieber, Ernst Peter; Riethmüller, Gert; Schattenkirchner, Manfred; Krüger, Klaus

doi: 10.1002/art.1780340504pmid: 2025306

Recent experimental and clinical data point to the T helper lymphocyte subset as playing a central role in the pathogenesis of rheumatoid arthritis (RA). Thus, a therapeutic strategy aimed specifically at the CD4 T cell subset is warranted. We treated patients with active RA for 7 days with a daily dose of 20 mg of CD4 monoclonal antibody M‐T151, administered intravenously over 30 minutes. There were no negative side effects. According to changes in the combined parameters of Ritchie articular index, pain assessment, grip strength, and morning stiffness, 6 patients had a good response. Clinical improvement was greatest approximately 2 weeks after termination of the therapy and lasted from 4 weeks to 6 months. Of the serologic parameters of inflammation, only the C‐reactive protein level improved in the patients with a favorable response. Close immunologic monitoring revealed a transient, selective depletion of CD4+ T cells after each infusion. During the entire treatment period, residual circulating CD4+ cells were found to be coated with CD4 antibody, whereas free antibody was detected in the serum only for approximately 8 hours after each infusion. Immediately after infusion, soluble CD4 antigen appeared in the serum. In addition to the cell‐bound CD4 antibody, complement components could be detected on the surface of the remaining CD4+ cells. The proliferative response of peripheral blood mononuclear cells to purified protein derivative was significantly diminished 4 weeks after cessation of antibody treatment. Six patients showed a weak antibody response to mouse immunoglobulin. In 4 of the responders who received a second course of therapy (2 of them as outpatients), a therapeutic effect was noted that was similar to that after the first course. Only 1 patient, who had low titers of serum IgE anti‐mouse Ig antibodies, showed a mild anaphylactic reaction at the end of the second course of therapy. Treatment of RA with the monoclonal CD4 antibody M‐T151 seems to be a promising alternative, although the optimal dose and the regimen of administration are still to be defined.

Cooper, Sheldon M.; Dier, Douglas L.; Roessner, Karen D.; Budd, Ralph C.; Nicklas, Janice A.

doi: 10.1002/art.1780340505pmid: 2025307

The synovitis of rheumatoid arthritis (RA) is characterized by infiltrates of CD4+ T lymphocytes. To determine the clonal diversity of these cells, we cloned T cells with interleukin‐2 (IL‐2), alone or with phytohemagglutinin (PHA), directly from actively inflamed synovial tissue obtained at synovectomy. A total of 205 clones from 4 specimens was analyzed for T cell receptor (TCR) gene rearrangements using Hind III and Eco RI digests with β chain and γ chain complementary DNA probes. A comparison of the TCR rearrangements enabled us to determine if the T cell clones arose from the same or different precursor cells. Most of the T cell clones (92%) had distinct TCR gene rearrangement patterns, indicating a unique clonal origin. However, a few clones (1 quadruplicate and 6 pairs) with identical TCR rearrangements were identified, and these clonal multiples were most commonly found in clones selected with IL‐2 alone. Mass cultures were propagated with IL‐2, alone or with PHA, and at each passage, cells were removed for TCR analysis. The later passages of the lines selected with IL‐2 had oligoclonal TCR rearrangements, whereas no oligoclonal rearrangements were found in the PHA + IL‐2‐selected cell lines. The TCR rearrangements in the later passages of the IL‐2 mass cultures were often identical to the TCR rearrangements that were found in the IL‐2‐derived clonal multiples. These findings indicate that while the majority of CD4+ T cells within the actively inflamed rheumatoid joint have diverse clonal origins, small numbers of clonal multiples and oligoclonal populations are present, and these cells may be enriched in an IL‐2‐responsive T cell subset.

Gao, Xiaojiang; Stastny, Peter; Brautbar, Chaim; Naparstek, Y.; Gazit, Ephraim; Livneh, A.; Segal, Raphael

doi: 10.1002/art.1780340506pmid: 2025308

HLA–DR4 is associated with risk for developing rheumatoid arthritis (RA) in most populations. In Israeli Jews, in whom the Dw10 subtype of DR4 predominates, no association of RA with DR4 has been found. The inability to detect an association could be due to the high frequency of DR4‐Dw10. We used DNA typing with amplification by the polymerase chain reaction and dot‐blotting with allele‐specific oligonucleotides to determine DR4 variants in 131 Jewish RA patients living in Israel and 134 controls. In both Ashkenazi Jews and non‐Ashkenazi Jews, the rare variant Dw15 (previously identified in Japanese populations and in Japanese patients with RA) was found to be the main allele associated with the risk of developing RA (relative risk = 9.2, corrected P < 0.001). However, this low‐frequency allele could be responsible for susceptibility in only 11.5% of the patients. Susceptibility for rheumatoid factor–positive RA was associated with Dw4 and Dw15; the risk for rheumatoid factor–negative RA was associated only with Dw14. The distribution of the HLA–DQ alleles associated with DR4 showed that more than half of the RA patients with Dw15 also had HLA–DQw2. The frequencies of DQw7 and DQw8 were not different in RA patients compared with controls. The results suggest that, as in other populations, susceptibility for the development of RA in Israeli Jews is associated with DRB1 locus alleles of the DR4 group.

Russell, I. Jon; Fletcher, Ellen M.; Michalek, Joel E.; McBroom, Patrick C.; Hester, G. Gene

doi: 10.1002/art.1780340507pmid: 2025309

A multidimensional evaluation of 78 patients with primary fibrositis/fibromyalgia syndrome (PFS) revealed no significant relationship between clinical measures of physical discomfort and psychological measures. This observation provided evidence against the notion that the pain of PFS has a psychological etiology. The same patients were randomized into 4 groups for treatment with ibuprofen and/or alprazolam in a randomized, double‐blind, double‐dummy, placebo‐controlled pilot trial. Clinical improvement in patient rating of disease severity and in the severity of tenderness upon palpation was most apparent in the subgroup of patients who were receiving both ibuprofen and alprazolam. An 8‐week, open‐label study in which 52 patients received both drugs further documented improvement in outcome measures. These data indicate that treatment with a combination of ibuprofen and alprazolam can be beneficial for some patients with PFS.

Fox, David A.; Millard, Jo Ann; Treisman, Jonathan; Zeldes, Wendy; Bergman, Alice; Depper, Joel; Dunne, Robert; McCune, W. Joseph

doi: 10.1002/art.1780340508pmid: 1673843

CD2 (T11; sheep erythrocyte receptor) is the surface component of an alternative, antigen‐independent pathway of human T cell activation. The response to certain anti‐CD2 antibodies is relatively independent of accessory cell signals and therefore provides a direct measurement of T cell function. The CD2 pathway may be important in the differentiation of thymocytes, on which the expression of CD2 precedes the appearance of the CD3–T cell receptor complex. In view of the impaired T cell regulation of immune responses in patients with systemic lupus erythematosus (SLE), we examined the activation of peripheral blood lymphocytes by anti‐CD2 antibodies in 57 SLE patients and 32 normal control subjects. The CD2 pathway response was lower in the SLE patients (P < 0.0001); 18 of the 57 SLE patients had a lower response than any of the control subjects. The SLE low‐responder patients did not differ from the normal‐responder patients in terms of disease activity or use of antiinflammatory and immunosuppressive medications. Low responses to anti‐CD2 were corrected to normal by the coaddition of a submitogenic amount of phorbol myristate acetate (1 ng/ml). In some low‐responder patients, the responses were normalized by the removal of non–T cells. The data indicate that some SLE patients have impaired responses to CD2 pathway activation and that this may reflect intrinsic T cell defects and/or regulatory influences of non–T cells.

Hines, John J.; Elkon, Keith B.; Danho, Waleed

doi: 10.1002/art.1780340509pmid: 2025310

Anti‐Sm–positive sera from patients with systemic lupus erythematosus (SLE) recognize a major epitope located within the carboxyl‐terminal 27 amino acids of a recombinant SmB fusion protein. To determine whether a synthetic peptide corresponding to this region could be used as an antigen to detect anti‐Sm antibodies, sera were typed as anti‐Sm positive or anti‐Sm negative by counterimmunoelectrophoresis (CIE). Twenty‐three SLE sera that were anti‐Sm positive by CIE, 22 that were anti‐Sm negative by CIE, and 42 sera from patients with other autoimmune diseases were tested for anti‐Sm antibodies by enzyme‐linked immunosorbent assay (ELISA), using either the synthetic peptide (C27) or a recombinant SmB (rSmB) fusion protein as the antigen. More than 90% of the sera that were anti‐Sm positive by CIE were also positive by both the C27 and rSmB ELISAs, and an additional 2 SLE sera originally typed as anti‐Sm negative were found to be positive (1 by the C27 ELISA, 1 by the rSmB ELISA), due to the greater sensitivity of the ELISAs. In the rSmB ELISA, anti‐Sm antibodies were not detected in any of the sera from patients with other autoimmune diseases, whereas 3 patients with anti–U1 RNP antibodies (1 each with polymyositis, scleroderma, and mixed connective tissue disease) had a positive result in the C27 ELISA. These results indicate that both the C27 synthetic peptide and rSmB are excellent antigens for use in ELISAs to quantify anti‐Sm antibodies.