Rheumatoid Arthritis: Trollmo C

Malmström V, Trollmo C, Klareskog L. · Department of Medicine, Karolinska Institutet, Stockholm, Sweden. · Arthritis Res Ther. · Pubmed #15833144 No free full text.

Abstract: Rheumatoid arthritis (RA) is a common destructive inflammatory disease that affects 0.5-1% of the population in many countries. Even though several new treatments have been introduced for patients with RA, a considerable proportion of patients do not benefit from these, and the need for alternative treatment strategies is clear. This review explores the potential for a therapy targeting the adaptive immune system by modulating co-stimulation of T cells with a CTLA4-Ig fusion protein (abatacept).

Malmstrøm V, Trollmo C, Klareskog L. · Department of Medicine at Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden. · Am J Med Sci. · Pubmed #15084915 No free full text.

Abstract: The development of rheumatoid arthritis (RA) occurs as a result of interactions between genes and environment. The most well established association with both susceptibility and severity of disease is variations in the major histocompatibility complex (MHC) class II genes. This fact constitutes evidence in favor of a contribution from specific MHC class II restricted adaptive immunity to the pathogenesis of RA. However, considerable difficulties have been encountered in identifying reactivities within the adaptive immune system that are responsible for the development of chronic arthritis in humans. In this article, the authors suggest a hypothesis for arthritis development based on their, as well as others', research. In patients with certain genetic contexts, RA can be initiated by activation of the innate immune system alone. In other patients, the adaptive immune system may be needed for the induction of disease. Additionally, the authors believe that a perpetuation to a severe chronic arthritis occurs only when both the adaptive and the innate immune systems have been recruited.

Vallerskog T, Heimbürger M, Gunnarsson I, Zhou W, Wahren-Herlenius M, Trollmo C, Malmström V. · Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet, CMM L8:04, Karolinska Hospital, SE-171 76 Stockholm, Sweden. · Arthritis Res Ther. · Pubmed #17092341 links to  free full text

Abstract: The objective of this study was to investigate the interaction between levels of BAFF (B-cell activation factor of the tumour necrosis factor [TNF] family) and APRIL (a proliferation-inducing ligand) and B-cell frequencies in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) treated with the B-cell-depleting agent rituximab. Ten patients with SLE were treated with rituximab in combination with cyclophosphamide and corticosteroids. They were followed longitudinally up to 6 months after B-cell repopulation. Nine patients with RA, resistant or intolerant to anti-TNF therapy, treated with rituximab plus methotrexate were investigated up to 6 months after treatment. The B-cell frequency was determined by flow cytometry, and serum levels of BAFF and APRIL were measured by enzyme-linked immunosorbent assays. BAFF levels rose significantly during B-cell depletion in both patient groups, and in patients with SLE the BAFF levels declined close to pre-treatment levels upon B-cell repopulation. Patients with SLE had normal levels of APRIL at baseline, and during depletion there was a significant decrease. In contrast, patients with RA had APRIL levels 10-fold higher than normal, which did not change during depletion. At baseline, correlations between levels of B cells and APRIL, and DAS28 (disease activity score using 28 joint counts) and BAFF were observed in patients with RA. In summary, increased BAFF levels were observed during absence of circulating B cells in our SLE and RA patient cohorts. In spite of the limited number of patients, our data suggest that BAFF and APRIL are differentially regulated in different autoimmune diseases and, in addition, differently affected by rituximab treatment.

Korotkova M, Westman M, Gheorghe KR, af Klint E, Trollmo C, Ulfgren AK, Klareskog L, Jakobsson PJ. · Rheumatology Research Laboratory, CMM L8-04, Karolinska Institutet, Karolinska University Hospital, Stockholm S-17176, Sweden. · Arthritis Rheum. · Pubmed #16255020 links to  free full text

Abstract: OBJECTIVE: Microsomal prostaglandin E synthase 1 (mPGES-1) is up-regulated in experimental arthritis and markedly expressed in synovial tissue biopsy samples from patients with rheumatoid arthritis (RA). This study was carried out to determine the effects of tumor necrosis factor (TNF) blockers and glucocorticoids on mPGES-1 and cyclooxygenase (COX) expression, as well as biosynthesis of PGE(2) in rheumatoid joints. METHODS: In vitro effects of TNF blockers and dexamethasone on the PGE(2) biosynthetic pathway were examined in RA synovial fluid mononuclear cells (SFMCs) by flow cytometry. PGE(2) levels in culture supernatants were measured by enzyme immunoassay. Expression of enzymes responsible for PGE(2) synthesis ex vivo was evaluated by immunohistochemistry in synovial biopsy samples obtained from 18 patients before and after treatment with TNF blockers and from 16 patients before and after intraarticular treatment with glucocorticoids. Double immunofluorescence was performed using antibodies against mPGES-1, COX-1, COX-2, and CD163. RESULTS: Double immunofluorescence revealed that mPGES-1 and COX-2 were colocalized in SFMCs as well as in RA synovial tissue cells. The addition of either TNF blockers or dexamethasone suppressed lipopolysaccharide-induced mPGES-1 and COX-2 expression in synovial fluid monocyte/macrophages in vitro and decreased the production of PGE(2). Intraarticular treatment with glucocorticoids significantly reduced both mPGES-1 and COX-2 expression in arthritic synovial tissue ex vivo. The number of COX-1-expressing cells in synovial tissue was also significantly decreased by glucocorticoid treatment. In contrast, neither mPGES-1 nor COX-2 expression in synovial tissue was significantly suppressed by anti-TNF therapy. CONCLUSION: These data are the first to demonstrate the effects of antirheumatic treatments on mPGES-1 expression in RA and suggest that the inhibition of PGE(2) biosynthesis, preferably by targeting mPGES-1, might complement anti-TNF treatment for optimal antiinflammatory results in RA.

Catrina AI, Trollmo C, af Klint E, Engstrom M, Lampa J, Hermansson Y, Klareskog L, Ulfgren AK. · Rheumatology Research Laboratory, CMM L8:04, Karolinska University Hospital, S-171 76 Stockholm, Sweden. · Arthritis Rheum. · Pubmed #15641091 links to  free full text

Abstract: OBJECTIVE: Treatment of rheumatoid arthritis (RA) with tumor necrosis factor (TNF) antagonists is highly effective, but their mechanisms of action are not completely clear. Since anti-TNF therapy induces a decrease in synovial cellularity, this study focused on the modulation of RA synovial apoptosis following treatment with either soluble TNF receptor (etanercept) or TNF chimeric monoclonal antibody (infliximab). METHODS: Apoptosis (TUNEL and active caspase 3 staining) and cell surface markers were evaluated by immunohistochemistry in synovial biopsy samples obtained before and after 8 weeks of treatment with etanercept (12 patients) or infliximab (9 patients). We also determined by flow cytometry the in vitro effect of etanercept and infliximab on apoptosis of RA mononuclear cells derived from the synovial fluid (SF) and peripheral blood (PB). RESULTS: Eight weeks of treatment with etanercept and with infliximab significantly increased synovial apoptosis. This change was accompanied by a significant decrease in the synovial monocyte/macrophage population. The decrease in lymphocyte numbers did not reach statistical significance. In vitro, 24 hours of incubation with either etanercept or infliximab induced apoptosis of the SF monocyte/macrophage population. PB monocyte/macrophages were less susceptible to anti-TNF-mediated apoptosis. No changes in the rate of apoptosis were observed in the lymphocyte population derived from either SF or PB. CONCLUSION: In RA patients, both etanercept and infliximab are able to induce cell type-specific apoptosis in the monocyte/macrophage population. This suggests a potential pathway that would account for the diminished synovial inflammation and the decreased numbers of synovial macrophages evident after TNF blockade.

Fasth AE, Snir O, Johansson AA, Nordmark B, Rahbar A, Af Klint E, Björkström NK, Ulfgren AK, van Vollenhoven RF, Malmström V, Trollmo C. · Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. · Arthritis Res Ther. · Pubmed #17825098 links to  free full text

Abstract: Expanded populations of CD4+ T cells lacking the co-stimulatory molecule CD28 (CD4+CD28null T cells) have been reported in several inflammatory disorders. In rheumatoid arthritis, increased frequencies of CD4+CD28null T cells in peripheral blood have previously been associated with extra-articular manifestations and human cytomegalovirus (HCMV) infection, but their presence in and contribution to joint manifestations is not clear. In the present article we investigated the distribution of CD4+CD28null T cells in the synovial membrane, synovial fluid and peripheral blood of RA patients, and analysed the association with erosive disease and anti-citrullinated protein antibodies. CD4+CD28null T cells were infrequent in the synovial membrane and synovial fluid, despite significant frequencies in the circulation. Strikingly, the dominant TCR-Vbeta subsets of CD4+CD28null T cells in peripheral blood were often absent in synovial fluid. CD4+CD28null T cells in blood and synovial fluid showed specificity for HCMV antigens, and their presence was clearly associated with HCMV seropositivity but not with anti-citrullinated protein antibodies in the serum or synovial fluid, nor with erosive disease. Together these data imply a primary role for CD4+CD28null T cells in manifestations elsewhere than in the joints of patients with HCMV-seropositive rheumatoid arthritis.

Cao D, Börjesson O, Larsson P, Rudin A, Gunnarsson I, Klareskog L, Malmström V, Trollmo C. · Rheumatology Unit, Department of Medicine at Karolinska University Hospital Solna, Karolinska Institutet, Stockholm. · Scand J Immunol. · Pubmed #16764698 No free full text.

Abstract: Regulatory T cells have recently been implicated in a number of human diseases, including rheumatoid arthritis. To investigate whether the presence of CD25+CD4+ regulatory T cells is a general finding in arthritic joints, synovial fluid of patients with different rheumatic diseases such as undifferentiated arthritides, systemic rheumatic diseases and reactive arthritis were investigated for the presence of such cells. In 95% of the patients, a higher frequency of CD25(bright)CD4+ T cells was found in synovial fluid as compared with peripheral blood. Both in vitro suppression experiments and FOXP3 mRNA analysis confirmed these cells to be natural regulatory T cells. Together with our previous data, we conclude that arthritic joints, irrespective of precise diagnosis and disease duration, are enriched with natural regulatory T cells. These results suggest that suppressor cells migrate to and/or multiply at the sites of inflammation as part of the immune responses' effort to combat injurious inflammation.

Fasth AE, Cao D, van Vollenhoven R, Trollmo C, Malmström V. · Rheumatology Unit, Department of Medicine, Karolinska Hospital, Karolinska Institutet, SE-171 76 Stockholm, Sweden. · Scand J Immunol. · Pubmed #15238090 No free full text.

Abstract: CD4+ T cells lacking the costimulatory molecule CD28 have been described both in elderly individuals and in chronic inflammatory disorders, one being rheumatoid arthritis (RA). We, in this study, provide a comprehensive characterization of cell surface markers on and function of such CD28nullCD4+ T cells, as well as correlations with clinical parameters. We conclude that of all surface markers associated with these cells, only CD57 and CD11b are expressed on the majority of them. This CD28null population occurred in one-third of patients with RA and was independent of clinical characteristics. The population was persistent and expanded in peripheral blood, but was excluded from the joint in most patients. Functionally, CD28nullCD4+ T cells were potent effector memory cells with regard to their proliferation and cytokine-secretion profiles. This capacity correlated with a hitherto unpublished surface phenotype, the cells being uniformly CCR7- and CD43high. Moreover, a new terminally differentiated CD45RA+CCR7- population of CD4+ T cells was identified. We would like to suggest that in the unbalanced immune system of patients with autoimmune disease and chronic infection an expanded CD28nullCD4+ T-cell population able to secrete high levels of cytokines is likely to contribute to disease manifestations.

Cao D, van Vollenhoven R, Klareskog L, Trollmo C, Malmström V. · Rheumatology Unit, Department of Medicine at Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden. <> · Arthritis Res Ther. · Pubmed #15225369 links to  free full text

Abstract: CD25+CD4+ regulatory T cells participate in the regulation of immune responses. We recently demonstrated the presence of CD25brightCD4+ regulatory T cells with a capacity to control T cell proliferation in the joints of patients with rheumatoid arthritis. Here, we investigate a possible accumulation of these regulatory T cells in the inflamed joint of different rheumatic diseases including rheumatoid arthritis. The studies are also extended to analyze whether cytokine production can be suppressed by the regulatory T cells. Synovial fluid and peripheral blood samples were obtained during relapse from 36 patients with spondyloarthropathies, 21 adults with juvenile idiopathic arthritis and 135 patients with rheumatoid arthritis, and the frequency of CD25brightCD4+ T cells was determined. Of 192 patients, 182 demonstrated a higher frequency of CD25brightCD4+ T cells in synovial fluid than in peripheral blood. In comparison with healthy subjects, the patients had significantly fewer CD25brightCD4+ T cells in peripheral blood. For functional studies, synovial fluid cells from eight patients were sorted by flow cytometry, and the suppressive capacity of the CD25brightCD4+ T cells was determined in in vitro cocultures. The CD25brightCD4+ T cells suppressed the production of both type 1 and 2 cytokines including interleukin-17, as well as proliferation, independently of diagnosis. Thus, irrespective of the inflammatory joint disease investigated, CD25brightCD4+ T cells were reduced in peripheral blood and enriched in the joint, suggesting an active recruitment of regulatory T cells to the affected joint. Their capacity to suppress both proliferation and cytokine secretion might contribute to a dampening of local inflammatory processes.

Cao D, Malmström V, Baecher-Allan C, Hafler D, Klareskog L, Trollmo C. · Unit of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. · Eur J Immunol. · Pubmed #12594850 No free full text.

Abstract: In the homeostasis of the immune system regulatory cells play a major role. Removal of one group of regulatory cells, the CD25(+)CD4(+) T cells, leads to autoimmune manifestations in experimental animal models, and reintroduction of this population prevents disease. This study addresses the role of such regulatory T cells in humans with an autoimmune disease, where we demonstrate the presence of CD25(bright)CD4(+) T cells in the target organ of patients with active rheumatoid arthritis. The patients displayed an enrichment of CD25(bright)CD4(+) T cells in synovial fluid as compared to peripheral blood. These cells are functional regulatory cells, as they were able to suppress in vitro proliferation of autologous T cells, both from synovial and peripheral blood origin. Although the frequency of CD25(bright)CD4(+) T cells varied between patients, it was found to be constant over time in any one joint during each relapse. Numbers were also comparable in two inflamed knee joints of one and the same patient, emphasizing the symmetry of the disease. In summary, it is striking that in addition to all activated, potentially pathological T cells the synovial fluid from RA patients also contains CD25-expressing CD4(+) T cells with a regulatory capacity.