Synovium as a source of increased amino-terminal parathyroid hormone-related protein expression in rheumatoid arthritis. A possible role for locally produced parathyroid hormone-related protein in the pathogenesis of rheumatoid arthritis.

Proinflammatory cytokines, including tumor necrosis factor (TNF) and interleukin 1 (IL-1), mediate the joint destruction that characterizes rheumatoid arthritis (RA). Previous studies have shown that parathyroid hormone-related protein (PTHrP) is a member of the cascade of proinflammatory cytokines induced in parenchymal organs during lethal endotoxemia. To test the hypothesis that NH2-terminal PTHrP, a potent bone resorbing agent, could also be a member of the synovial cascade of tissue-destructive cytokines whose expression is induced in RA, PTHrP expression was examined in synovium and synoviocytes obtained from patients with RA and osteoarthritis (OA). PTHrP production, as determined by measurement of immunoreactive PTHrP(1-86) in tissue explant supernatants, was increased 10-fold in RA versus OA synovial tissue. Synovial lining cells and fibroblast-like cells within the pannus expressed both PTHrP and the PTH/PTHrP receptor, findings that were confirmed by in vitro studies of cultured synoviocytes. TNF-alpha and IL-1beta stimulated PTHrP expression in synoviocytes, while dexamethasone and interferon-gamma, agents with some therapeutic efficacy in the treatment of RA, inhibited PTHrP release. Treatment of synoviocytes with PTHrP(1-34) stimulated IL-6 secretion. These results suggest that proinflammatory cytokine-stimulated production of NH2-terminal PTHrP by synovial tissue directly invading cartilage and bone in RA may mediate joint destruction through direct effects on cartilage or bone, or, indirectly, via the induction of mediators of bone resorption in the tumor-like synovium.

Anchorage-independent growth of synoviocytes from arthritic and normal joints. Stimulation by exogenous platelet-derived growth factor and inhibition by transforming growth factor-beta and retinoids.

Exuberant tumor-like synovial cell proliferation with invasion of periarticular bone is a feature of rheumatoid arthritis in humans and of streptococcal cell wall (SCW)-induced arthritis in rats. These histologic observations prompted us to examine synoviocytes from arthritic joints for phenotypic characteristics of transformed cells. The capacity to grow in vitro under anchorage-independent conditions is a characteristic that correlates closely with potential in vivo tumorigenicity. In medium supplemented with 20% serum or in basal media supplemented with platelet-derived growth factor (PDGF), early passage synoviocytes from both SCW-induced and rheumatoid arthritic joints formed colonies in soft agarose. Epidermal growth factor (EGF), interleukin 1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and transforming growth factor-beta (TGF-beta) did not support growth, although EGF enhanced PDGF-dependent growth. On the other hand, TGF-beta, as well as all-trans-retinoic acid, inhibited colony growth. Early passage normal rat and human synoviocytes also grew under the same conditions, but lung, skin, and late-gestation embryonic fibroblast-like cells did not. Considered in the context of other published data our findings provide cogent evidence that synoviocytes, but not other types of fibroblast-like cells, readily acquire phenotypic characteristics commonly associated with transformed cells. Expression of the transformed phenotype in the inflammatory site is likely regulated by paracrine growth factors, such as PDGF and TGF-beta.

Streptococcal myositis.

Two patients had streptococcal myositis. Both patients developed extensive muscle necrosis and overwhelming sepsis after trivial skin trauma. Death occurred within 48 hours of hospital admission despite aggressive surgical and medical treatment. Review of the literature is included to highlight the fulminant nature of this unusual infection and to contrast streptococcal myositis with other soft-tissue streptococcal infections.

Lack of preferential V beta usage in synovial T cells of rheumatoid arthritis patients.

The T-cell receptor V beta subfamily repertoires of synovial and peripheral T cells of 8 rheumatoid arthritis (RA) patients were determined using the polymerase chain reaction. Three normal controls were included. Some of the rheumatoid synovial samples did not express the complete range of V beta families and lacked as many as 6 gene families. However, these patients showed considerable individual variation in expression. Overall, the data do not support preferential T-cell receptor V beta usage in synovial T cells of RA patients either in comparison to their autochthonous peripheral T cells or to peripheral T cells of normal subjects.

Hydroxychloroquine in the treatment of rheumatoid arthritis.

One hundred eight patients with rheumatoid arthritis received hydroxychloroquine for six to 24 months and were studied retrospectively to examine long-term efficacy and predictors of a favorable response to the drug. Response was classified in terms of reduction of active joint count and morning stiffness. Thirteen patients (12 percent) showed a complete remission. Fifteen patients (14 percent) had a 75 percent or greater response. Forty patients (37 percent) had a 30 to 75 percent response. Thirty-two (30 percent) had no response. Toxicity occurred in eight patients (7 percent) before clinical efficacy could be assessed. Seven of the 68 with response had a flare of disease after initial improvement. Of multiple clinical and laboratory parameters tested, only a stronger baseline grip strength was found to be statistically significant (p less than 0.001) in predicting a favorable response. Thus, hydroxychloroquine is an effective drug in the management of rheumatoid arthritis.

Budd-Chiari syndrome and renal failure in Behcet disease. Report of a case and review of the literature.

A case of Behcet syndrome associated with three rare complications is presented. The patient initially presented with asymmetric polyarticular arthritis, subcutaneous nodules, conjunctivitis, and episcleritis. Necrotizing vasculitis and renal failure subsequently evolved. Despite immunosuppressive therapy, Budd-Chiari syndrome with high grade hepatic obstruction developed. A Denver shunt procedure failed to alter the terminal course. At postmortem examination, skin lesions, carditis, hepatic vein thrombosis, gastric ulcerations, and focal proliferative glomerulonephritis were found. The immunoglobulins and complement present in skin and renal tissue suggest an immune complex pathogenesis.

Combination therapy with cyclosporin in rheumatoid arthritis.

During the last few years, there have been rapid developments in the drug treatment of rheumatoid arthritis. This has led to research into the role of combination therapy. While past combinations of slow-acting antirheumatic drugs have resulted in either an excessive number of adverse events or a lack of increased efficacy over single agent therapy, newer combinations appear to be more promising. It has recently been demonstrated that the combination of cyclosporin and methotrexate is more effective than methotrexate alone, with no increase in adverse effects. Improved trial methodology and a better understanding of the mechanism of action of these newer agents are assisting in the development of new combinations.

Cyclosporine in rheumatoid arthritis: beyond experimentation.

The potential for combined therapy in rheumatoid arthritis is rapidly increasing considering the recent development of various new treatment modalities. However, an aggressive effort must be made to stage patients according to various clinical and immunological parameters. Only then can appropriate combined therapy be used effectively in this disease process. The development of such combined therapy could expand into other diseases such as scleroderma, systemic lupus erythematosus, and multiple sclerosis.

The use of immunomodulators in early rheumatoid arthritis.

Immunomodulators represent a unique class of drugs that are not biologics, usually are isolated from nature, and have relatively specific noncytotoxic effects on the immune system. Although most slow-acting antirheumatic drugs (SAARDs) have effects on the immune system, these effects usually are not specific, often are cytotoxic, are not associated with specific cellular binding proteins, and their effect on immunity is difficult to correlate with their clinical effects. Most immunomodulators primarily affect T cells; because of their apparent role in rheumatoid arthritis (RA), studies of these agents are appropriate. Cyclosporine, the most widely tested of the immunomodulators, has shown significant efficacy in established RA in studies worldwide. However, only one study using cyclosporine has been performed in relatively early RA, in which the most positive effects might be expected. FK506 and rapamycin, agents similar to cyclosporine, are being tested in human transplantation; the only arthritis studies have been performed in animals. Tilomisole, imuthiol, and mycophenolate mofetil have been studied in limited RA trials, with positive effects. However, no trials have been conducted in early RA. Although promising, this class of drugs will require more studies to establish their efficacy and safety, especially in early RA.

T cells: pathogenic cells and therapeutic targets in rheumatoid arthritis.

OBJECTIVES: To provide: 1) a brief review of current thought on the role of T cells in the pathogenesis of rheumatoid arthritis (RA); and 2) To provide an overview of RA therapies directed against T cells. METHODS: The following papers in relevant American and European medical journals were reviewed. Those related to: the role of T cells in the pathogenesis of RA; to biological therapy directed against cell surface markers specific to T cell populations implicated in RA; and to treatment of RA with cyclosporin A and leflunomide, pharmacological agents known to interfere with the T cell response to antigens. RESULTS: Although a variety of cell types are now recognized as contributors to the progressive joint destruction that is a hallmark of RA, T cell activation is still thought to be a central event in the initiation and progression of this disease. As a result, various therapeutic options directed against T cells have been developed. These include biological agents directed against specific populations of activated T cells and pharmacological agents that have specific T cell-modulatory actions. CONCLUSIONS: Use of T cell-directed biological therapies for RA has been disappointing, as a result of both lack of efficacy and serious toxicity. Treatment of RA with pharmacological agents that interfere with antigen-driven T cell proliferation has been more successful.

Cyclosporine, FK-506, rapamycin, and other immunomodulators.

Immunomodulatory agents represent a unique group of therapies that are not biologics and have relatively specific, noncytotoxic effects on the immune system. Cyclosporine has been the most widely tested of the immunomodulatory agents and shown efficacy in a variety of autoimmune diseases as well as monotherapy in established rheumatoid arthritis. FK-506 and rapamycin, agents similar to cyclosporine, are being tested in human transplantation, with only arthritis studies having been done in animals. Tilomisole, imuthiol, and mycophenolate mofetil have been studied in limited rheumatoid arthritis trials with positive effects. Although more specific and with manageable short-term side effects, this group of therapies requires more studies to establish their efficacy and long-term safety.

Cyclosporine in rheumatoid arthritis.

Rheumatoid arthritis is a chronic inflammatory process of unknown etiology that leads to significant morbidity and accelerated mortality in the 10 to 15% of patients with severe proliferative and erosive synovitis that is unresponsive to conventional therapies. T cells play a key role in the initiation and perpetuation of the process. Based on its immune action, cyclosporine has been used in rheumatoid arthritis in a variety of worldwide clinical trials. This article presents the results of several pivotal studies and outlines the development of cyclosporine in the treatment of rheumatoid arthritis.

Exercise, education, and behavioral modification as alternative therapy for pain and stress in rheumatic disease.

Stress and pain mechanisms are complex and share many central nervous system pathways. Both are critical issues for patients with rheumatoid arthritis and other connective tissue diseases. The link between stress and neuroendoimmune function suggests that alternative therapies focusing on improved psychologic and metabolic function could significantly change patients' pain outcomes. Programs using alternative therapies such as tai chi and meditation in combination with traditional medications appear to be beneficial for patients with arthritis. These individuals appear to live better lives and may have better long-term outcomes.

Inhibition by cyclosporin A of streptococcal cell wall-induced hepatic granulomas in LEW/N rats.

A single intraperitoneal injection of an aqueous suspension of group A streptococcal cell wall fragments into susceptible LEW/N female rats results in the development of noncaseating hepatic granulomas as a consequence of deposition and persistence of the cell walls in the liver. We have studied the effect of daily intramuscular injections of CS-A, an inhibitor of T lymphocyte activation, on granuloma formation. CS-A-treatment resulted in the pronounced inhibition of granuloma formation, although no appreciable differences in quantity of streptococcal cell wall antigens, which were deposited in the liver, could be demonstrated. These data suggest that activated T lymphocytes play a key role in the pathogenesis of this granulomatous process.

Mechanisms of bone and cartilage destruction in rheumatoid arthritis: lessons from the streptococcal cell wall arthritis model in LEW/N rats.

Rheumatoid arthritis is a proliferative and erosive disease which has been described as tumor-like. Streptococcal cell wall-induced arthritis in the LEW/N rat is also tumor-like and closely simulates the features of joint destruction that develop in rheumatoid arthritis. This article discusses the mechanisms of bone and cartilage destruction in streptococcal cell wall arthritis with particular emphasis on the tumor-like behavior of synovial connective tissue cells and the role of cytokines, such as platelet-derived growth factor, transforming growth factor beta and interleukin 1, in regulating this abnormal behavior.

Naturally occurring human autoantibodies to defined T-cell receptor and light chain peptides.

We used synthetic peptides duplicating the structures of a human lambda light chain (Mcg), and a human T-cell receptor (Tcr) alpha and a Tcr beta chain predicted from gene sequence to determine the presence and loci of activity of natural human autoantibodies directed against these antigen recognition molecules. We report that normal individuals and patients suffering from autoimmune diseases have antibodies directed against regions of lambda light chains and Tcr beta chains corresponding to the first complementarity determining region and the third framework region of the variable domain and to constant region determinants. The levels of IgM natural antibodies particularly against the CDR1 peptides tend to be higher in RA patients than in normals or SLE patients. Although polyclonal IgG immunoglobulins from healthy individuals did not show detectable reactivity to Tcr alpha peptides, such reactivity was found in the IgM immunoglobulins of RA patients, thereby showing that Tcr alpha peptides can be autoantigenic in man. The levels of IgM autoantibodies to V beta CDR1 peptides tend to decrease with age. By contrast, there was a marked increase in IgG natural autoantibodies to certain CDR1 sequences with advancing age. We suggest that the natural antibodies to defined regions of immunoglobulins and T-cell receptors are part of a physiological network for the regulation of the immune response.

Autoregulation of Tcr V region epitopes in autoimmune disease.

Normal individuals possess low levels of autoantibodies specific for certain peptide defined regions of T-cell receptor (Tcr) variable regions, particularly CDR1 and Fr3. These regions are predicted to be exposed on the surface of the native molecule and, by analogy and comparison with immunoglobulins, correspond to public idiotype determinants. The anti-Tcr idiotype antibodies appear to be ubiquitous and we propose that they play a role in the regulation of T-cell function. To delineate the parameters of expression of these antibodies, we characterized anti-Tcr antibody activity in normal individuals, in those suffering from the autoimmune diseases rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), and in patients with non-autoimmune arthritis (osteoarthritis) as a disease control. There were significant increases in autoantibody levels in the autoimmune patients. There was also variation in isotype and the particular variable regions recognized. IgM autoantibodies directed against a few peptide defined determinants were elevated in RA, whereas SLE patient sera showed high levels of IgG binding to a broad spectrum of Tcr peptides.

Epitope promiscuity of human monoclonal autoantibodies to T-cell receptor-combining site determinants.

To characterize the binding specificity and light- and heavy-chain variable region usage in monoclonal human autoantibodies (mAAbs) to T-cell receptors, we constructed heterohybridomas from peripheral blood B cells of three rheumatoid arthritis (RA) patients. From a panel of more than 200 heterohybridomas secreting IgM autoantibodies binding to T-cell receptor Vbeta chain first complementarity determining segments (CDR1), we characterized two IgM/lambda molecules from a single patient in detail. These bound to both CDR1 peptide epitopes and intact TCR of recombinant single-chain T-cell receptor constructs, and to T-cell surface TCR. Spectratype analysis using epitopes mimicking a set of 24 Vbeta genes indicated that one molecule bound only a few members of the set, whereas the second showed considerable epitope promiscuity by binding to more than half of the tested CDR1 peptides. Both mAAbs used variants of a Vlambda3 gene that were very similar to one another and to the germline gene. The epitope-promiscuous autoantibody used a V(H)4 gene identical to a germline prototype, while the other incorporated a V(H)3 sequence differing in only a single residue from its germline prototype. The CDR3s of both were large and distinct from each other as well as from the corresponding segments of rheumatoid factors and "cold agglutinins" using the same or related V(H) germline genes. These mAAbs offer models for deciphering the basis of epitope promiscuity, and serve as candidates for direct use in immunomodulation because they are of intrinsic human origin and do not require molecular engineering to adapt them for use in therapy.

Combination therapy with cyclosporine in rheumatoid arthritis.

The role of combination therapy in rheumatoid arthritis is increasing with the recent development of various new treatment modalities. While past combinations of slow acting antirheumatic drugs have resulted in either excessive side effects or lack of efficacy over single agent therapy, recent combinations appear more promising. Recently, the combination of cyclosporine and methotrexate (MTX) was shown to be more efficacious than MTX alone. Improved methodology and a better understanding of the mechanisms of action of these newer agents is responsible for these exciting results.