Rheumatoid Arthritis: Eklund KK

Eklund KK. · Division of Rheumatology, Helsinki University Central Hospital, Helsinki, Finland. · Immunol Rev. · Pubmed #17498050 No free full text.

Abstract: Increasing evidence suggests that mast cells (MCs), in addition to acute allergic reactions, are involved in the pathogenesis of chronic inflammatory diseases and in particular in rheumatoid arthritis (RA). MCs reside in connective tissues and in synovial tissue of joints. They produce an array of proinflammatory mediators, tissue destructive proteases, and cytokines, most prominently tumor necrosis factor-alpha, which is one of the key cytokines in the pathogenesis of RA. MCs may also participate in the development of secondary or amyloid A amyloidosis, as the partial degradation of the serum amyloid A (SAA) protein by MCs leads to the generation of a highly amyloidogenic N-terminal fragment of SAA. MCs may contribute to the pathogenesis of connective tissue diseases, scleroderma, vasculitic syndromes, and systemic lupus erythematosus, although the data available are limited. Inhibition of the most important growth factor receptor of human MCs, c-Kit, by the selective tyrosine kinase inhibitor imatinib mesylate, induces apoptosis of synovial tissue MCs. As MCs are long-lived cells, induction of their apoptosis could be a feasible approach to inhibit their functions. Preliminary findings suggest that a drug that inhibits c-Kit could have anti-rheumatic activity in the treatment of patients with RA and spondyloarthropathies.

Eklund KK, Lindstedt K, Sandler C, Kovanen PT, Laasonen L, Juurikivi A, Wolff H, Mykkänen M, Joensuu H. · Department of Medicine, Division of Rheumatology, Helsinki University Central Hospital, Helsinki, Finland. · J Clin Rheumatol. · Pubmed #18824923 No free full text.

This publication has no abstract.

Eklund KK, Leirisalo-Repo M, Ranta P, Mäki T, Kautiainen H, Hannonen P, Korpela M, Hakala M, Järvinen P, Möttönen T. · Department of Medicine, Division of Rheumatology, Helsinki University Central Hospital, Helsinki, Finland. · Clin Exp Rheumatol. · Pubmed #18078614 No free full text.

Abstract: OBJECTIVE: To study interleukin (IL)-1beta levels in recent onset RA patients treated either with combination DMARD therapy (sulfasalazine, methotrexate, hydroxychloroquine) or a single DMARD therapy. METHODS: Serum IL-1beta levels were measured before the treatment and 6 months after the institution of either single or combination DMARD therapy using a high sensitivity ELISA method. Radiographic evaluation of the hands and feet was performed at 0 and 24 months. RESULTS: Significant correlations (r = 0.28, 95% CI 0.10-0.45) were found between IL-1beta levels measured at 0 and 6 months. The IL-1beta levels at 0 months correlated significantly (r = 0.23, 95% CI 0.03-0.4, p= 0.021) with the baseline number of eroded joints at 0 months but not with radiographic joint damage at 24 months. The baseline level of IL-1beta was a better indicator for the presence of eroded joints than the baseline level of serum CRP. No significant changes in IL-1beta levels were observed during the first 6 months of anti-rheumatic treatment in either group. No statistically significant difference between IL-1beta levels in the patients with or without the shared epitope could be observed. CONCLUSIONS: The serum IL-1beta level is significantly associated with the presence of erosions at the onset of RA but its predictive value is attenuated or lost when single or combination DMARD medication is instituted. Measuring IL-1beta at the time of diagnosis in a single patient cannot be used to estimate the erosive nature of the disease or the prognosis.

Sandler C, Lindstedt KA, Joutsiniemi S, Lappalainen J, Juutilainen T, Kolah J, Kovanen PT, Eklund KK. · Department of Medicine, Division of Rheumatology, Helsinki University Central Hospital, Kasarmikatu 11-13, 00130 Helsinki, Finland. · Inflamm Res. · Pubmed #17607547 No free full text.

Abstract: OBJECTIVES AND DESIGN: To study the consequences of mast cell activation in human synovial tissue. METHODS: Synovial tissue was obtained from 18 RA patients and mast cells was selectively activated in synovial tissue explant cultures. Expression of TNF-alpha, IL-1beta and IL-1Ra were determined and tissue distribution of IL-1beta was studied. RESULTS: Compared to untreated synovia, selective activation of synovial mast cells increased significantly the production of TNF-alpha (0.49 +/- 0.88 vs. 4.56 +/- 3.18 pg/mg wet tissue, p < 0.001) and IL-1beta (0.058 +/- 0.032 vs. 2.55 +/- 1.98 pg/mg wet tissue, p = 0.013). The expression of TNF-alpha and IL-1beta mRNA increased significantly (19-fold (p = 0.009) and 13-fold (p = 0.031), respectively). Mast cell activation induced IL-1beta expression in particular in nearby CD68 positive synovial macrophages. Secretion of IL-1Ra was also increased but to a lesser degree than that of IL-1beta. CONCLUSIONS: Synovial mast cells produce proinflammmatory cytokines and may thus contribute to the inflammation in RA.

Sandler C, Joutsiniemi S, Lindstedt KA, Juutilainen T, Kovanen PT, Eklund KK. · Department of Medicine, Division of Rheumatology, Helsinki University Central Hospital, Finland. · Biochem Biophys Res Commun. · Pubmed #16806061 No free full text.

Abstract: Synovial fibroblast is the key cell type in the growth of the pathological synovial tissue in arthritis. Here, we show that platelet-derived growth factor (PDGF) is a potent mitogen for synovial fibroblasts isolated from patients with rheumatoid arthritis. Inhibition of PDGF-receptor signalling by imatinib mesylate (1muM) completely abrogated the PDGF-stimulated proliferation and inhibited approximately 70% of serum-stimulated proliferation of synovial fibroblasts. Similar extent of inhibition was observed when PDGF was neutralized with anti-PDGF antibodies, suggesting that imatinib mesylate does not inhibit pathways other than those mediated by PDGF-receptors. No signs of apoptosis were detected in synovial fibroblasts cultured in the presence of imatinib. These results suggest that imatinib mesylate specifically inhibits PDGF-stimulated proliferation of synovial fibroblasts, and that inhibition of PDGF-receptors could represent a feasible target for novel antirheumatic therapies.

Sandler C, Nurmi K, Lindstedt KA, Sorsa T, Golub LM, Kovanen PT, Eklund KK. · Department of Medicine, Division of Rheumatology, Helsinki University Central Hospital, Kasarmikatu 11-13, 00130 Helsinki, Finland. · Int Immunopharmacol. · Pubmed #16039551 No free full text.

Abstract: Chemically modified tetracyclines are a group of non-antimicrobial tetracycline derivatives, which possess antiinflammatory, anticollagenolytic and antiproliferative properties. Here we studied the effects of four different chemically modified tetracyclines (CMT-1, CMT-3, CMT-8 and CMT-308) on proliferation and viability of cultured mouse and human mast cells. All studied CMTs (25 microM) effectively inhibited the viability and proliferation of human mast cell line (HMC-1) cells and mouse bone marrow derived mast cells (mBMMCs), as judged by trypan blue exclusion and by incorporation of [(3)H]thymidine. The antiproliferative effect of CMTs was not dependent on the stimulating growth factor, i.e. CMTs inhibited both IL-3 and c-kit ligand-induced proliferation of mBMMCs. The reduced viability of mast cells was due to induction of apoptosis, as indicated by the increased amount of apoptotic nucleosomes and the appearance of TUNEL positive cells in the presence of CMTs. The induction of apoptosis was further confirmed by showing that CMT-3 induces activation of caspase-3 and caspase-9 in HMC-1 cells. Additionally, CMT-3 induced downregulation of the expression of antiapoptotic Bcl-2 protein in HMC-1 cells. Compared to doxycycline, the antiproliferative and proapoptotic effects of different CMTs were clearly more pronounced. Of the studied CMTs, CMT-3 and CMT-8 appeared to be the most potent inhibitors of mast cell proliferation and survival. The present results show that CMTs have an antiproliferative and proapoptotic effect on both malignant and non-malignant mast cells. In conclusion, CMTs could offer a novel means to treat disorders with inappropriate expansion of mast cells, such as rheumatoid arthritis and systemic mast cell diseases.

Juurikivi A, Sandler C, Lindstedt KA, Kovanen PT, Juutilainen T, Leskinen MJ, Mäki T, Eklund KK. · Division of Rheumatology, Helsinki University Central Hospital, Kasarmikatu 11-13, 00130 Helsinki, Finland. · Ann Rheum Dis. · Pubmed #16014680 links to  free full text

Abstract: BACKGROUND: Mast cells have been implicated in the pathogenesis of arthritis, but elucidation of their precise role has been hampered by a lack of efficient and selective inhibitors of their function. OBJECTIVE: To elucidate the role of mast cells in the pathogenesis of rheumatoid arthritis (RA) and to assess whether apoptosis of cultured and synovial tissue mast cells can be induced by inhibiting mast cell growth factor receptor, c-kit tyrosine kinase. METHODS AND RESULTS: Double staining with tumour necrosis factor (TNF) alpha and tryptase antibodies showed the presence of TNFalpha positive mast cells in human rheumatoid synovial tissue. Selective activation of mast cells by anti-IgE resulted in production of TNFalpha in synovial tissue cultures. Inhibition of the c-kit tyrosine kinase with imatinib mesylate (1.0-10 micromol/l) induced profound apoptosis in cultured mast cells as judged by typical apoptotic morphology, increased number of apoptotic nucleosomes, and activation of caspases 8 and 9. Importantly, imatinib also induced apoptosis of mast cells in explant cultures of synovial tissue obtained from patients with RA as judged by a TUNEL assay. Inhibition of c-kit tyrosine kinase was accompanied by significant reduction of TNFalpha production in synovial tissue cultures. CONCLUSION: Mast cells may have a role in the pathogenesis of RA, and inhibition of c-kit may be a new means of inhibiting mast cell activity and of abrogating the contribution of mast cells to synovial inflammation in RA.

Eklund KK, Joensuu H. · Department of Internal Medicine, Division of Rheumatology, Helsinki University Central Hospital, Helsinki, Finland. · Ann Med. · Pubmed #12952023 No free full text.

Abstract: BACKGROUND: Imatinib mesylate is an inhibitor of a few tyrosine kinases including KIT, which is an important growth factor receptor of mast cells. AIM: To study the efficacy and safety of imatinib in the treatment of rheumatoid arthritis. METHOD: Three patients with severe rheumatoid were treated with imatinib for 12 weeks. The number of tender and swollen joints, patient-assessed disease activity and pain as assessed by a visual analogue scale, a health assessment questionnaire (HAQ) score, serum C-reactive protein (CRP) and blood erythrocyte sedimentation rate (ESR) were used as the primary outcome measures. RESULTS: All outcome measures improved. The swollen joint count decreased in all patients, and the tender joint count in two of the three patients. The patients reported less pain and disease activity, and the HAQ scores improved. Serum CRP and blood ESR improved in two patients. One patient interrupted therapy due to a rash. CONCLUSIONS: Imatinib mesylate may have considerable anti-rheumatic efficacy. The mechanism of action is not known, but one possible target for the action of imatinib is inhibition of the KIT receptor on mast cells.

Eklund KK, Anttila P, Leirisalo-Repo M. · No affiliation provided · Scand J Rheumatol. · Pubmed #15080271 No free full text.

This publication has no abstract.

Eklund KK, Peltomaa R, Leirisalo-Repo M. · No affiliation provided · Clin Exp Rheumatol. · Pubmed #14611130 No free full text.

This publication has no abstract.