Osteonecrosis in the rheumatoid femoral head.

OBJECTIVE: To define the prevalence and pathological spectrum of femoral head osteonecrosis in patients with rheumatoid arthritis (RA) and to correlate its presence with disease related clinical and therapeutic factors. METHODS: A total of 545 primary total hip arthroplasties performed in 507 patients with RA were identified. A historical review of each patient's rheumatoid disease and treatment as well as pathological review of each femoral head specimen was performed. RESULTS: Osteonecrosis was identified in 66 specimens (12.1%) in one of 2 discrete forms. Thirty-two specimens (5.9%) contained classic subchondral avascular necrosis. Thirty-four specimens (6.2%) contained osteonecrosis in association with degenerative changes (within regions of sclerotic and eburnated subchondral bone), but not classic avascular necrosis. Remaining femoral head specimens were characterized by inflammatory arthritis (431 specimens) or degenerative joint disease (48 specimens). Corticosteroid therapy was used in 81% of patients with avascular necrosis and 68% with degenerative osteonecrosis. This was significantly greater prevalence than in patients without osteonecrosis (33%). Average daily prednisone dosage was 8 mg and no association between dosage and the presence of osteonecrosis was identified. No correlation between pathological findings and clinical disease severity was identified. In 5 of 27 specimens showing classic avascular necrosis and 11 of 34 containing degenerative osteonecrosis, no steroid treatment had been administered. CONCLUSION: Femoral head osteonecrosis is present in about 12% of patients with RA at hip arthroplasty, and occurs in 2 forms -- classic avascular necrosis and degenerative necrosis. Both forms are significantly associated with corticosteroid use. "Low dose" therapy does not protect patients against the development of osteonecrosis. Additionally, baseline prevalence of osteonecrosis of about 3% occurs in the absence of steroid use and may be related to the underlying inflammatory diseases. Despite its association with osteonecrosis the net effect of corticosteroid therapy on the natural history of rheumatoid hip disease remains unclear.

IL-6/IFN-beta 2 in synovial effusions of patients with rheumatoid arthritis and other arthritides. Identification of several isoforms and studies of cellular sources.

We have looked for IL-6, a cytokine that has immunomodulating and inflammation-associated activities, in joint exudates (fluid and mononuclear cells) from patients with rheumatoid arthritis and other arthritides using both biologic and biochemical assays. IL-6 was assessed by its ability to stimulate alpha 1-antichymotrypsin secretion from the human hepatoma cell line Hep3B clone 2, an activity which is blocked by an antiserum to Escherichia coli derived IL-6, and by the growth of the IL-6-dependent murine hybridoma 7TD1 cell line. IL-6 isoforms in synovial fluid were characterized by immunoaffinity chromatography followed by Western blotting. The presence of IL-1 in synovial fluids and its production by synovial fluid mononuclear cells was monitored by Western blotting and indirect immunofluorescence with polyclonal anti-IL-1 beta antisera. In an analysis of 30 effusions from 27 rheumatoid patients with acutely inflamed joints, abundant quantities of IL-6 (greater than 2 ng/ml) were detected in 23 by the alpha 1-antichymotrypsin bioassay. Several rheumatoid synovial fluids also had elevated IL-6 levels in the 7TD1 bioassay. Seven of nine nonrheumatoid effusions also contained high levels of IL-6 (greater than 2 ng/ml). No IL-1 (less than 0.25 ng/ml) could be detected by Western blotting in 10 rheumatoid effusions even though eight of these contained high levels of IL-6. The IL-6 activity could be neutralized with a rabbit antiserum to rIL-6. Multiple IL-6 isoforms (25, 30, 45 kDa) were present in two rheumatoid and one traumatic effusion studied. Fresh mononuclear cells isolated from various synovial effusions did not appear to make IL-6 constitutively, as no IL-6 could be detected in the media of cells cultured for 12 to 18 h after isolation. Similarly, there was no constitutive production of IL-1 by these cells. However, synovial fluid mononuclear cells could be induced to secrete both IL-6 and IL-1 after stimulation with LPS. The LPS-responsive cells were monocytes and not lymphocytes or dendritic cells. These findings suggest that IL-6 is involved in inflammatory joint disease. However, the primary cells synthesizing it may be located in the synovial lining instead of the joint exudate.

Interleukin-1 production by mononuclear cells from rheumatoid synovial effusions.

The polypeptide interleukin-1 (IL-1) is a cytokine that may mediate inflammation and connective tissue damage in rheumatoid arthritis (RA). We examined cytokine production by normal blood and by rheumatoid synovial mononuclear cells with sensitive (picomolar) assays. The assays were immunolabeling and immunoblotting with rabbit anti-IL-1 beta sera, and proliferation of the murine D10 cell line to IL-1. Little or no cytokine was detected in rheumatoid joint fluid or in exudate mononuclear cells from patients with acute rheumatoid flares. The mononuclear cells could be induced to make IL-1 upon stimulation with lipopolysaccharide (LPS). The responsive cells were monocytes, since all could be double-labeled with anti-IL-1 and the monocyte-specific CD14 antibody. More than 80% of the synovial fluid monocytes made IL-1 beta after 24 hr in 2 ng/ml LPS. Other agents failed to induce IL-1 from enriched populations of monocytes including interferon gamma (IFN-gamma), poly (I/C), phorbol myristate acetate (PMA), concanavalin A (Con A), phytohemagglutinin (PHA), and anti-CD3 antibodies. Relatively high levels of dendritic cells (DC) were present in RA effusions, but these did not produce IL-1 in response to any of the above stimuli. Blood dendritic cells also did not make IL-1, whereas blood monocytes responded comparably to synovial exudate cells. The data indicate that rheumatoid exudate monocytes make very little IL-1 during acute flares of arthritis and that this cytokine is primarily a macrophage rather than a dendritic cell product.

Identification of immunostimulatory dendritic cells in the synovial effusions of patients with rheumatoid arthritis.

Dendritic cells in the circulation are leukocytes that are rich in Ia antigens and that actively stimulate T cell replication. We have identified dendritic cells in the joint effusions of patients with rheumatoid arthritis. By phase-contrast and immunofluorescence microscopy, synovial mononuclear cells contained 1-5% dendritic profiles that were rich in HLA-DR and DQ, had small amounts of C3bi receptor, and lacked a battery of monocyte and lymphocyte markers. These dendritic cells could be enriched to 60-80% purity by cytolytic depletion of monocytes and lymphocytes with a group of monoclonal antibodies (MAb) and complement. By transmission electron microscopy, the dendritic cell processes were bulbous in shape and lacked organelles. The cytoplasm had few lysosomes or endocytic vacuoles but contained a well-developed smooth reticulum that was comparable to that previously described in the Ia-rich interdigitating cells of lymphoid tissues. The growth of sodium periodate-modified T lymphocytes was used as a rapid quantitative assay of accessory cell function. Synovial mononuclear cells were some ten times more active than normal blood cells. Treatment with alpha-Ia MAb and complement ablated stimulatory function. In contrast, removal of monocytes (MAb, 3C10) or monocytes and B (MAb, BA-1) plus T (MAb, OKT3, or T101) lymphocytes did not significantly alter total activity, and the function per viable cell increased four- to eightfold. We conclude that rheumatoid arthritis synovial fluids contain cells that are comparable in function, phenotype, and structure to blood dendritic cells, although the frequency (1-5%) is 10 times greater in joints. The reason for their accumulation in the articular cavity is not known, but dendritic cells may be important in perpetuating the joint inflammation characteristic of this disease.

Juvenile ankylosing spondylitis.

The clinical histories and radiographs of 28 patients with ankylosing spondylitis were reviewed. Symptoms developed before the age of 17 in all cases. Juvenile ankylosing spondylitis affected youths in their early teens, who presented most commonly with appendicular joint complaints rather than low back pain. The disease was progressive, with the characteristic changes of ankylosing spondylitis eventually occurring in the spine and sacroiliac joints, frequently accompanied by widespread and severe changes in the appendolar joints. HLA B 27 antigen was present in 8 of the 9 patients tested. Thorough clinical, radiographic, and laboratory examination should prevent confusion with juvenile rheumatoid arthritis.