Analysis of cytokine mRNA and protein in rheumatoid arthritis tissue revealed that many proinflammatory cytokines such as TNF alpha, IL-1, IL-6, GM-CSF, and chemokines such as IL-8 are abundant in all patients regardless of therapy. This is compensated to some degree by the increased production of anti-inflammatory cytokines such as IL-10 and TGF beta and cytokine inhibitors such as IL-1ra and soluble TNF-R. However, this upregulation in homeostatic regulatory mechanisms is not sufficient as these are unable to neutralize all the TNF alpha and IL-1 produced. In rheumatoid joint cell cultures that spontaneously produce IL-1, TNF alpha was the major dominant regulator of IL-1. Subsequently, other proinflammatory cytokines were also inhibited if TNF alpha was neutralized, leading to the new concept that the proinflammatory cytokines were linked in a network with TNF alpha at its apex. This led to the hypothesis that TNF alpha was of major importance in rheumatoid arthritis and was a therapeutic target. This hypothesis has been successfully tested in animal models, of, for example, collagen-induced arthritis, and these studies have provided the rationale for clinical trials of anti-TNF alpha therapy in patients with long-standing rheumatoid arthritis. Several clinical trials using a chimeric anti-TNF alpha antibody have shown marked clinical benefit, verifying the hypothesis that TNF alpha is of major importance in rheumatoid arthritis. Retreatment studies have also shown benefit in repeated relapses, indicating that the disease remains TNF alpha dependent. Overall these studies demonstrate that analysis of cytokine expression and regulation may yield effective therapeutic targets in inflammatory disease.

leads to a pro-inflammatory response remains to be and Ravinder N. Maini determined. To obtain clues about the important anti-Kennedy Institute of Rheumatology gens recognized, T cell receptor expression in RA joints Hammersmith has been extensively studied, but early reports of re-London, W6 8LW stricted T cell receptor usage have not been confirmed. United KingdomThe nature of the autoantigens recognized by autoantigen reactive T cells in rheumatoid arthritis are not known, although collagen type II (Ronnelid et al., 1994), a major protein of hyaline cartilage, and other chondro-Rheumatoid arthritis (RA) is a common human autoimcyte/cartilage proteins, as well as the heat shock protein mune disease with a prevalence of about 1%. While HSP70 have been suggested. Much progress will bethere has been progress in defining its etiology and come possible when the important T cell epitopes are pathogenesis, these are still incompletely understood defined, as it will open up the possibility of inducing (Ziff, 1990). Like many autoimmune diseases it is more antigen specific therapy, such as immunological tolfrequent in women, suggesting a role for sex hormones.erance. Rheumatoid arthritis is characterized by a chronic in-However, the role of T lymphocytes in established RA flammation of the synovial joints and infiltration by is incompletely understood. Based on the lack of T cell blood-derived cells, chiefly memory T cells, macrophages, and plasma cells, all of which show signs of proliferation and low levels of T cell derived cytokines activation, (Janossy et al., 1981; Cush and Lipsky, 1988).detectable in RA joints, Firestein and Zvaifler (1990) sug-This leads in most cases to progressive destruction of gested that T cells may not be important in perpetuating cartilage and bone, which occurs after invasion of these disease at the late stages. This possibility is supported tissues by the cellular synovial tissue and is believed to by the disappointing results of therapeutic trials of be mainly mediated by cytokine induction of destructive agents designed to diminish T cell function in late-stage enzymes, chiefly matrix metalloproteinases. There is RA patients: depleting antibodies to CD4, CDW52, and also prominent development of new vessels and evi-CD7, as well as immunotoxins directed to IL-2 receptor dence of systemic inflammation, for example, upreguor CD5 expressing cells (e.g., van der Lubbe et al., 1995; lated acute phase proteins. In more severe cases there Kirkham et al., 1992;Moreland et al., 1995; Olsen et is involvement of vessels and other organs. Mortality is al., 1994) have only yielded moderate or no benefit in increased in patients with severe rheumatoid arthritis placebo controlled studies. Since there are two major (Pincus and Callahan, 1993). A diseased joint showing subsets of of helper (CD4ϩ) T cell function (Th1 cells the major cell types and sites of joint destruction is producing the pro-inflammatory mediators IL-2 and illustrated in Figure 1.IFN␥ and Th2 cells producing IL-4, which has anti-in...

A large number of cytokines are active in the joints of patients with rheumatoid arthritis (RA). It is now clear that these cytokines play a fundamental role in the processes that cause inflammation, articular destruction, and the comorbidities associated with RA. Following the success of TNF-α blockade as a treatment for RA, other cytokines now offer alternative targets for therapeutic intervention or might be useful as predictive biomarkers of disease. In this Review, we discuss the biologic contribution and therapeutic potential of the major cytokine families to RA pathology, focusing on molecules contained within the TNF-α, IL-1, IL-6, IL-23, and IL-2 families.

Although there have been major advances in the treatment of rheumatoid arthritis with the advent of biological agents, the mechanisms that drive cytokine production and sustain disease chronicity remain unknown. Tenascin-C (encoded by Tnc) is an extracellular matrix glycoprotein specifically expressed at areas of inflammation and tissue damage in inflamed rheumatoid joints. Here we show that mice that do not express tenascin-C show rapid resolution of acute joint inflammation and are protected from erosive arthritis. Intra-articular injection of tenascin-C promotes joint inflammation in vivo in mice, and addition of exogenous tenascin-C induces cytokine synthesis in explant cultures from inflamed synovia of individuals with rheumatoid arthritis. Moreover, in human macrophages and fibroblasts from synovia of individuals with rheumatoid arthritis, tenascin-C induces synthesis of proinflammatory cytokines via activation of Toll-like receptor 4 (TLR4). Thus, we have identified tenascin-C as a novel endogenous activator of TLR4-mediated immunity that mediates persistent synovial inflammation and tissue destruction in arthritic joint disease.

Objective. To evaluate the safety and efficacy of a chimeric monoclonal antibody to tumor necrosis factor a (TNFa) in the treatment of patients with rheumatoid arthritis (RA).Methods. Twenty patients with active RA were treated with 20 mg/kg of anti-TNFa in an open phase YII trial lasting 8 weeks.Results. The treatment was well tolerated, with no serious adverse events. Significant improvements were seen in the Ritchie Articular Index, which fell from a median of 28 at study entry to a median of 6 by week 6 (P < 0.001), the swollen joint count, which fell from 18 to 5 (P < 0.001) over the same period, and in the other major clinical assessments. Serum C-reactive protein levels fell from a median of 39.5 mg/liter at study entry to 8 mghiter at week 6 (P < 0.001), and significant decreases were also seen in serum amyloid A and interleukin-6 levels.Conclusion. Treatment with anti-TNFa was safe and well tolerated and resulted in significant clinical and laboratory improvements. These preliminary results support the hypothesis that TNFa is an important regulator in RA, and suggest that it may be a useful new therapeutic target in this disease.

No abstract

Solitary fibrous tumors are rare tumors that occur at all anatomic sites. Most SFT patients fare well after surgical treatment. Closer surveillance is warranted for those tumors that are larger than 10 cm or with the presence of a histologically malignant component.

The presence and the role of interleukin 10 (IL-10), a potent cytokine synthesis inhibitory factor and antiinflammatory cytokine, were investigated in rheumatoid arthritis (RA). The expression of both mRNA and protein for IL-10 could be demonstrated in RA and osteoarthritis (OA) joints. Human IL-10 mRNA could be demonstrated by polymerase chain reaction amplification of cDNA made by reverse transcription of total RNA extracted directly from synovial tissue in five out of five RA and four out of five OA patients. IL-10 protein was demonstrated by specific immunoassay and immunohistology. IL-10 protein was spontaneously produced in all 11 RA and 17 OA synovial membrane cultures investigated, and this production was sustained for up to 5 d in culture in the absence of any extrinsic stimulation. IL-10 protein could also be detected by immunohistology in all five RA and four OA synovial membrane biopsies investigated, but not three normal synovial membranes. Immunohistology revealed that the IL-10 was localized to the synovial membrane lining layer and mononuclear cell aggregates. Immunofluorescence double staining revealed that the sources of IL-10 were monocytes in the lining layer, and T cells in the mononuclear cell aggregates. We found evidence that the IL-10 expression was functionally relevant, as neutralization of endogenously produced IL-10 in the RA synovial membrane cultures resulted in a two- to threefold increase in the protein levels of proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and IL-1 beta, although IL-6 and IL-8 levels were not affected. The addition of exogenous recombinant IL-10 to the RA synovial membrane cultures resulted in a two- to threefold decrease in the levels of TNF-alpha and IL-1 beta. IL-8 levels were reduced by day 5; however, IL-6 levels were not affected by exogenous IL-10. Neutralization of the endogenous IL-10 in two out of seven RA synovial membrane cultures resulted in the expression of detectable levels of interferon gamma (561-1,050 pg/ml). Taken together, the above findings suggest that IL-10 is spontaneously produced in RA and OA and is an important immunoregulatory component in the cytokine network of RA, regulating monocyte and in some cases T cell cytokine production.