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ID PMID Title PublicationDate abstract
12960481 New concepts in the pathogenesis of Sjögren syndrome: many questions, fewer answers. 2003 Sep Although a modified European-American consensus classification of Sjögren syndrome has been introduced during the last year, the etiopathogenesis of this disease characterized by chronic lymphocytic inflammation, impaired function, and, finally, destruction of the salivary and lacrimal glands as well as systemic manifestations remains to be elucidated. Recent insights into the pathogenesis of Sjögren syndrome resulting from immunogenetic, hormonal, and epidemiologic evaluations as well as animal and in vitro studies are highlighted by this review. Evidence confirms that lymphocytic disturbances, including ectopic germinal center formation and aberrations of cellular signaling play a significant role in Sjögren syndrome. Although some of these features are unique to Sjögren syndrome, others are also found in a number of systemic autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. The underlying cause of Sjögren syndrome remains largely enigmatic. However, distinct characteristics may provide the basis for the classification of the disease entities. Finally, an enhanced risk of lymphomagenesis is a well-known hallmark of primary Sjögren syndrome, indicating the central role of derangement of lymphocyte regulation. As demonstrated by the introduction of the new targeted therapeutic approaches in rheumatoid arthritis, solid insights into the pathogenesis of Sjögren syndrome may pave the way toward new therapeutic approaches.
14678197 Impact of cAMP on the T-cell response to type II collagen. 2004 Jan There is considerable interest in the possible use of cAMP-elevating agents in the treatment of autoimmune diseases such as rheumatoid arthritis. The objective of this study was to evaluate the impact of different cAMP-elevating agents on the T-cell response to type II collagen within the context of collagen-induced arthritis, a murine model of rheumatoid arthritis. Spleen cells or lymph node cells from type-II-collagen-immunized DBA/1 mice were cultured in the presence of type II collagen plus one of five different cAMP-elevating agents: rolipram, forskolin, prostaglandin E2, 8-bromo-cAMP, or cholera toxin. Levels of interferon-gamma (IFN-gamma), interleukin-4 (IL-4) and IL-5 were measured in culture supernatants by enzyme-linked immunosorbent assay. All of the cAMP-elevating agents tested were found to profoundly suppress IFN-gamma production in a dose-dependent manner. IL-4 and IL-5 production was slightly up-regulated at low concentrations of the cAMP-elevating agents and was modestly suppressed at the highest concentrations of cAMP-elevating agents. Experiments were then carried out to determine whether T cells were directly affected by cAMP-elevating agents or whether the immunomodulatory effects were mediated via antigen-presenting cells. Pulsing T cells alone for a brief period with cholera toxin produced an almost identical effect to pulsing antigen-presenting cells alone, i.e. down-regulation of proliferation, down-regulation of IFN-gamma production with little effect on IL-5 production. It was concluded that cAMP-elevating agents suppressed T helper type 1 responses to type II collagen to a greater extent than T helper type 2 responses. The cAMP-elevating agents could directly influence the activity of T cells but, in addition, influenced the ability of antigen-presenting cells to support T helper type 1 responses.
12124856 Benefit of an extract of Tripterygium Wilfordii Hook F in patients with rheumatoid arthrit 2002 Jul OBJECTIVE: To examine the safety and efficacy of an extract of Tripterygium wilfordii Hook F (TWHF) in the treatment of patients with rheumatoid arthritis (RA). METHODS: An ethanol/ethyl acetate extract from the roots of TWHF was prepared and used in a prospective, double-blind, placebo-controlled study in patients with longstanding RA in whom conventional therapy had failed. Patients were randomly assigned to receive either placebo or low-dose (180 mg/day) or high-dose (360 mg/day) extract for 20 weeks, followed by an open-label extension period. Clinical responses were defined as 20% improvement in disease activity according to the American College of Rheumatology criteria. Side effects were actively queried and recorded at each visit. RESULTS: A total of 35 patients were enrolled in the trial; 21 patients completed the 20-week study. One patient from each group withdrew because of side effects. Twelve, 10, and 10 patients in the placebo, low-dose, and high-dose groups, respectively, completed at least 4 weeks of treatment. Of these patients, 8 and 4 in the high-dose and low-dose groups, but none in the placebo group, met criteria for clinical response. Four, 4, and 7 patients in the placebo, low-dose, and high-dose groups, respectively, were enrolled in the open-label extension; of these, 2, 4, and 5 patients, respectively, met criteria for clinical response. The most common side effect was diarrhea, which caused 1 patient in the high-dose group to withdraw from the trial. No patients withdrew because of adverse events during the open-label extension. CONCLUSION: The ethanol/ethyl acetate extract of TWHF shows therapeutic benefit in patients with treatment-refractory RA. At therapeutic dosages, the TWHF extract was well tolerated by most patients in this study.
15125796 Arthritis induces lymphocytic bone marrow inflammation and endosteal bone formation. 2004 Jun Arthritis can destroy the cortical bone barrier and expose bone marrow to synovial tissue. This study examines bone marrow changes in arthritis and its effects on cortical bone remodeling. Bone marrow next to arthritic lesions exhibits B-lymphocyte-rich infiltrates, which express BMPs and stimulate endosteal bone formation. Thus, bone marrow actively participates in the arthritic process. INTRODUCTION: Imaging studies have shown that bone marrow changes occur in patients with rheumatoid arthritis (RA). To examine whether bone marrow is affected during arthritis, human TNF transgenic (hTNFtg) mice, which constitute an established animal model of human RA, were examined for bone marrow changes. MATERIALS AND METHODS: The hind paws (tarsal area) of 22 untreated hTNFtg mice, 5 hTNFtg mice treated with anti-TNF (infliximab), and 5 wildtype (WT) mice were examined histologically, immunohistochemically, and by means of mRNA in situ hybridization. RESULTS AND CONCLUSIONS: All untreated hTNFtg mice with moderate (n = 10) and severe (n = 7) disease developed inflammatory bone marrow lesions during the course of disease, whereas no such lesions appeared in hTNFtg mice with mild disease (n = 5) and WT mice. Bone marrow infiltrates were almost exclusively composed of lymphocytes, and the overwhelming proportion (>80%) was B-cells. Presence and extent of bone marrow infiltrates were closely linked to severity of arthritis. In addition, blockade of TNF effectively reduced bone marrow inflammation. Interestingly, osteoblast numbers were increased at the endosteal surface in the vicinity of these lesions. Moreover, osteoid deposition; expression of bone matrix proteins, such as osteocalcin and osteopontin; and mineralization were enhanced, suggesting that inflammatory bone marrow infiltrates induce bone formation. Indeed, B-lymphocytes of these lesions expressed bone morphogenetic protein (BMP)-6 and -7, which are important stimulators of new bone formation. Thus, we conclude that bone marrow actively participates in destructive arthritis by generating B-lymphocyte-rich bone marrow lesions and inducing endosteal bone formation.
12854885 Structure of synovial lymphatic capillaries in rheumatoid arthritis and juvenile idiopathi 2003 The structure of lymphatic capillaries (LC) of the synovial membrane (SM) from patients with rheumatoid arthritis and juvenile idiopathic arthritis obtained by synovectomy was investigated by transmission electron microscopy. This method allows comparison of the structure of the same vessel under light and electron microscope and clear differentiation between lymphatic and blood capillaries and venules. Synovial LC were localized in the subintimal connective tissue of the SM in the vicinity of venules. The shape of some LC was irregular, suggesting edema of the interstitium. Lymphatic endothelium has extremely attenuated cytoplasm with the exception of the perinuclear region. Many nuclei of endothelial cells had distinct nucleoli. The basal lamina was discontinuous. The walls of LC showed close connection with the interstitium represented by anchoring filaments that were attached to the endothelial cells and to the surrounding connective tissue. In some LC connective tissue appeared to be disconnected from endothelium and gaps between their walls and the interstitium were seen. Mononuclear cells were accumulated adjacent to some LC. Specialized interendothelial junctions (endothelial microvalves) were observed in the LC walls. Their structure and function in the migration of cells and debris from synovial interstitium into LC lumina in rheumatoid arthritic synovium deserves further investigation. In the lumina of some of the LC lymphocytes, monocytes, macrophages, cell debris and enlarged endothelium were observed. Accumulation of such material may cause obstruction of tiny LC. We suggest that reported alterations of the fine synovial lymphatic vessels can contribute to the progression of the inflammatory process to chronicity.
12734885 Therapeutic implications for interferon-alpha in arthritis: a pilot study. 2003 May OBJECTIVE: To evaluate the therapeutic potential of interferon-a (IFN-a) in osteoarthritis (OA) and rheumatoid arthritis (RA) by examining regulation of cytokine antagonist expression. METHODS: Expression of interleukin 1 receptor antagonist (IL-1Ra) and soluble tumor necrosis factor receptor (sTNFR) was examined by ELISA in cells from freshly isolated synovial fluids (SF) and synovial tissues (ST) from patients with OA or RA, either left untreated or treated with IFN-a. Single (7) and paired (5) SF and ST cells from OA and RA patients were examined. As well, the ability of IFN-a to regulate gene expression levels for osteoprotegerin (OPG) and osteoprotegerin ligand (OPGL) was examined in freshly isolated SF cells from patients with RA, by reverse transcriptase polymerase chain reaction. RESULTS: IL-1Ra and sTNFR were found to be constitutively expressed in OA and RA SF and ST cells. IFN-a treatment resulted in an increase in both IL 1Ra and sTNFR production. Freshly isolated RA SF cells exhibited constitutive OPGL gene expression in both the non-T and T cell fractions of the SF. In contrast, OPG gene expression levels were undetectable or low. IFN-a treatment of RA SF cells resulted in upregulation of OPG gene expression in the T cell fraction of the RA SF cells, whereas OPGL gene expression remained unaffected. CONCLUSION: These in vitro data suggest a therapeutic role for IFN-a in the treatment of arthritis through upregulation of critical cytokine antagonists.
15736919 Olive oil and modulation of cell signaling in disease prevention. 2004 Dec Epidemiological studies show that populations consuming a predominantly plant-based Mediterranean-style diet exhibit lower incidences of chronic diseases than those eating a northern European or North American diet. This observation has been attributed to the greater consumption of fruits and vegetables and the lower consumption of animal products, particularly fat. Although total fat intake in Mediterranean populations can be higher than in other regions (ca. 40% of calories), the greater proportion is derived from olive oil and not animals. Increased olive oil consumption is implicated in a reduction in cardiovascular disease, rheumatoid arthritis, and, to a lesser extent, a variety of cancers. Olive oil intake also has been shown to modulate immune function, particularly the inflammatory processes associated with the immune system. Olive oil is a nonoxidative dietary component, and the attenuation of the inflammatory process it elicits could explain its beneficial effects on disease risk since oxidative and inflammatory stresses appear to be underlying factors in the etiology of these diseases in man. The antioxidant effects of olive oil are probably due to a combination of its high oleic acid content (low oxidation potential compared with linoleic acid) and its content of a variety of plant antioxidants, particularly oleuropein, hydroxytyrosol, and tyrosol. It is also possible that the high oleic acid content and a proportionate reduction in linoleic acid intake would allow a greater conversion of alpha-linolenic acid (18:3n-3) to longer-chain n-3 PUFA, which have characteristic health benefits. Adoption of a Mediterranean diet could confer health benefits in high-risk populations.
12426847 [Technical aspects and value of arthrosonography in rheumatologic diagnosis. 4: Ultrasound 2002 Aug Musculoskeletal ultrasonography is an important imaging technique in the diagnosis of rheumatic diseases especially for early manifestation. It allows sensitive detection of small joint fluid collections as well as differentiation of soft tissue lesions and bone lesions. The following standard scans are suggested for sonographic evaluation of the elbow: 1) anterior humeroradial longitudinal scan, 2) anterior humeroulnar longitudinal scan to detect effusions, synovial proliferation, loose joint bodies, bone lesions (osteoarthritis/arthritis), 3) anterior transverse scan over the trochlea to evaluate these structures in an additional dimension, 4) posterior longitudinal scan and 5) posterior transverse scan of the olecranon fossa with flexed/extended elbow to evaluate the same objectives as the above mentioned scans and additionally to detect olecranon bursitis, and optional 6) distal dorsal longitudinal scan to differentiate soft tissue lesions such as rheumatoid nodules or gout tophi, 7) anterior transverse scan over the radius head to evaluate lesions of the radius head, tendopathy, calcinosis, 8) lateral humeroradial longitudinal scan to evaluate epicondylitis, 9) medial humeroulnar longitudinal scan to evaluate calcinosis, epicondylitis, signs of compression of the ulnar nerve. A linear transducer with a frequency of about 5-7.5 MHz is recommendable. The anterior distance between trochlea and the capitulum of the humerus between the bone and the joint-capsule of the elbow is > or = 2 mm in probable and > or = 3 mm in definite synovitis or effusions. Synovitis or effusions are probable if the difference between the right and left elbow is 1 mm, and they are definite if the difference is > or = 2 mm.
12794781 The cost effectiveness of rofecoxib and celecoxib in patients with osteoarthritis or rheum 2003 Jun 15 OBJECTIVE: To evaluate the cost effectiveness of the cyclooxygenase 2 (COX-2) selective nonsteroidal antiinflammatory drug (NSAID) rofecoxib compared with naproxen and the COX-2 NSAID celecoxib compared with ibuprofen and diclofenac. METHODS: Cost-effectiveness analysis based on a 5-year Markov model. Probability estimates were derived from detailed data of 2 randomized trials and a systematic search of the medical literature. Utility estimates were obtained from 60 randomly selected members of the general public. Cost estimates were obtained from Canadian provincial databases. Incremental cost-effectiveness ratios were calculated for patients at average risk of upper gastrointestinal (UGI) events and for high-risk patients with a prior history of a UGI event. Subjects were patients with osteoarthritis or rheumatoid arthritis (RA) where a decision has been made to treat with NSAIDs but who do not require low-dose aspirin. Main outcome measures were proportion of patients with clinical or complicated UGI events, quality-adjusted life expectancy, and life expectancy. RESULTS: Evaluation of rofecoxib versus naproxen in patients with RA at average risk resulted in costs per quality-adjusted life year (QALY) gained of $Can271,188. Celecoxib was dominated by diclofenac in average-risk patients. Both rofecoxib and celecoxib are cost-effective in high-risk patients. Analyses by age groups and assuming a threshold of Can$50,000 per QALY gained, suggest that rofecoxib or celecoxib would be cost-effective in patients aged over 76 and 81, respectively, without additional risk factors. CONCLUSION: Both rofecoxib and celecoxib are economically attractive in high risk and elderly patients. They are not economically attractive in patients at average risk. Coprescription of proton-pump inhibitors with COX-2 NSAIDs is not economically attractive for patients at high risk.
15621577 Anti-cyclic citrullinated peptide antibodies are highly associated with severe bone lesion 2004 Sep In the present study we investigated the predictive value of anti-cyclic citrullinated peptide antibodies (anti-CCP) in early rheumatoid arthritis (RA) with respect to the bone damage. Fifty-four patients with early RA (onset <12 months), 35 classified as established RA (onset >12 months), 33 healthy donors and 76 non-RA autoimmune diseases, were enrolled. Anti-CCP and IgG, IgA, IgM rheumatoid factors (RFs) were determined at baseline. Disease activity score (DAS 28) was calculated at the entry. Bone involvement was evaluated by X-rays and sonography. The specificity of anti-CCP was 98.4%; significantly higher than those of the IgM- (86.0%), IgA- (86.0%) and IgG-RFs (66.2%), respectively. Anti-CCP were detected in 23/54 (42.6%) early RA patients and in 16/35 (45.7%) established RA patients. In the early RA group, 6/33 (18.2%) of the patients without bone lesions, 12/16 (75%) with juxta-articular osteoporosis (JO) and 5/5 with joint erosions (JE) resulted positive showing a significant difference between the groups without and with radiological damage. In the established RA group a significant difference being between the group without radiological damage and that with JE was found. Finally, in patients without radiological lesions, examined by ultrasound, anti-CCP antibodies were detected only in subjects with pathologic findings (31.25%). Data here reported confirm that the presence of anti-CCP are specific for diagnosis of RA, of recent onset also and they are potentially useful as prognostic index of bone involvement.
12447637 Comparison of synovial MMP-1 and TIMP-1 levels in patients with various inflammatory arthr 2002 Nov The purpose of this study was to investigate synovial levels of matrix metalloproteinase-1 (MMP-1), known to break down collagen, and tissue inhibitor of metalloproteinase (TIMP-1), its natural antagonist, in patients with various inflammatory disorders. Eighty-five patients with different inflammatory arthritides (20 Behçet's disease, 20 familial Mediterranean fever, 26 rheumatoid arthritis and 19 osteoarthritis) were enrolled in the study. Synovial MMP-1 and TIMP-1 levels were measured by two-step sandwich ELISA. There were significant differences between study and control groups regarding erythrocyte sedimentation rate, C-reactive protein, MMP-1 and TIMP-1 values. The synovial MMP-1 levels of patients with Behçet's disease and familial Mediterranean fever were no different from those in patients with rheumatoid arthritis, but significantly higher than those of patients with osteoarthritis. The synovial TIMP-1 levels in patients with osteoarthritis were higher than those of patients with the other three diseases, among which the difference was not statistically significant, and the difference between osteoarthritis and the others was statistically significant. Because of the detection of similar levels of synovial MMP-1 in patients with familial Mediterranean fever, Behçet's disease and rheumatoid arthritis, we conclude that the absence of erosions in patients with familial Mediterranean fever and Behçet's disease may be explained by MMP-1 being a marker of cytokine-driven inflammation, or by the short-lived and transient nature of the arthritis observed in these patients.
15690699 [Analysis of the acid glycoprotein heterogeneity in patients with arthritis]. 2004 Oct The concentration measurement of the acute phase proteins in blood serum has been applied in differential diagnosis of inflammatory arthritis since a long time. However, it appeared that the qualitative changes such as the presence of different glycoforms of the acute phase protein that was a glycoprotein, enabled to differentiate acute inflammatory conditions including the chronic ones, and to determine the dynamics of inflammatory process. This phenomenon is defined as a main heterogeneity, whereas the determination of the proportions of particular glycoforms is known as glycosylation profile. The changes of this profile are well known in the course of acute inflammatory conditions such as: bacterial sepsis, skin burns complicated with bacterial infections or acute pancreatitis. Considerably less observations concern the chronic conditions as: rheumatoid arthritis, systemic lupus erythematosus and degenerative joint disease. The examination encompassed 25 patients with rheumatoid arthritis, 21 with systemic lupus erythematosus, 19 with reactive arthritis and 21 patients with degenerative joint disease whose diagnosis was established on the basis of international diagnostic criteria. In all these patient the changes of C-reactive protein (CRP), acid glycoprotein (AGP) as well as glycosylation profile of the AGP were evaluated. For this purpose the electrophoresis method of two affinity directions with concanavalin A was applied, whereas the concentration of particular acute phase protein was determined by Laurell's immunoelectrophoresis method. The variants of glycoprotein resulted from electrophoresis were calculated with aid of planimetric method, and the results were presented as a coefficient of glycosylation. The characteristic patterns of glycosylation profile in the course of systemic lupus erythematosus, rheumatoid arthritis and reactive arthritis may be useful in differential diagnosis of the above mentioned diseases.
15077295 Cyclooxygenase 2-derived prostaglandin E2 production by corticotropin-releasing hormone co 2004 Apr OBJECTIVE: To determine a mechanism by which corticotropin-releasing hormone (CRH) promotes human inflammatory joint disease progression. METHODS: An ex vivo synovial tissue culture system was established to investigate the functional properties of CRH at peripheral sites of inflammation. CRH- and interleukin-1 beta (IL-1 beta)-induced prostaglandin E(2) (PGE(2)) production from 10 fresh rheumatoid arthritis (RA) synovial tissue (ST) explants was quantified using a competitive enzyme-linked immunosorbent assay. Modulation of PGE(2) levels was further examined following selective and nonselective cyclooxygenase 2 (COX-2) inhibition. Nuclear extracts were analyzed by electrophoretic mobility shift assays to determine functional cAMP response element binding protein (CREB) activity in response to CRH and PGE(2) in isolated primary synovial cell populations. Western blot analysis measured levels of total and activated (phosphospecific) CREB/activating transcription factor (ATF) family members prior to and following stimulation. RESULTS: CRH, in a time- and dose-dependent manner, significantly (P = 0.022) up-regulated PGE(2) production from 10 fresh RA ST explants. Costimulation of RA ST with CRH and IL-1 beta significantly augmented (P = 0.036) the effects on PGE(2) production additively over 24 hours. We demonstrated that selective COX-2 inhibitors prevent the induction of PGE(2) by both CRH and IL-1 beta. Further, we provided evidence that CRH and PGE(2) signal through the induction of CREB and phosphorylated CREB/ATF family members in RA ST and in isolated primary RA cell populations. CONCLUSION: Our findings underscore the pathogenic role that CRH may play in modulating inflammatory joint disease and establish the CREB/ATF family of transcription factors as principal effector molecules of proinflammatory mediator action in RA.
15320917 Excitatory amino acids, TNF-alpha, and chemokine levels in synovial fluids of patients wit 2004 Sep The aim of this study was to assess the synovial fluid (SF) neurotransmitter excitatory amino acid (EAA) levels, including glutamate (Glu) and aspartate (Asp), in the context of SF levels of other amino acids, TNF-alpha and chemokines from patients with active arthropathies. The SF was collected from patients with active rheumatoid arthritis (RA), gout, or osteoarthritis (OA). The SF samples were analysed for levels of neurotransmitters glutamate and aspartate, tumour necrosis factor-alpha (TNF-alpha), Regulated upon Activation Normally T-cell Expressed and Secreted (RANTES), macrophage inhibitory factor-1 alpha (MIP-1alpha) and interleukin 8 (IL-8). SF WBC counts were also determined. Correlations between SF EAA, TNF-alpha and chemokines were determined by the Pearson product-moment correlation. Primary cultures derived from SF from active RA and gout patients were incubated with added l-glutamate, to assess if exposure to Glu could increase TNF-alpha levels. There were significant elevations in SF EAA, SF TNF-alpha and SF RANTES in RA patients compared to gout or OA patients. Significant correlations between SF EAA and SF RANTES, MIP-1alpha and IL-8 levels were seen, and SF EAA and SF TNF-alpha or SF WBC levels approached significance. Addition of exogenous neurotransmitter glutamate significantly increased TNF-alpha levels in primary cell cultures derived from RA and gout patients. The SF neurotransmitter EAA levels significantly correlated to selected SF chemokine levels, in clinically active RA, gout and OA patients, independent of disease. Added Glu resulted in significantly increased TNF-alpha levels in primary synovial cell cultures. These data expand the relationship of SF neurotransmitter EAA levels to SF cytokines and chemokines in patients with clinically active arthritis, and suggest that neurotransmitters Glu and Asp contribute to peripheral inflammatory processes.
14719189 Elevated serum nitric oxide levels in patients with inflammatory arthritis associated with 2003 Dec OBJECTIVE: To quantify circulating nitric oxide (NO) levels and inducible NO synthase (iNOS) expression in peripheral blood monocyte-derived macrophages (PB-MDM) from patients with inflammatory arthritis (IA) as a measure of disease activity, and to determine if there is a correlation between expression of iNOS and protein kinase C-eta (PKC-eta). METHODS: PB-MDM were isolated from whole blood of 20 patients with IA (14 rheumatoid arthritis and 6 peripheral spondyloarthropathies). Thirteen patients with osteoarthritis (OA) and 9 healthy individuals were controls. Serum NO levels were measured by indirect determination of nitrite and nitrate. Expression of PKC-eta and iNOS was investigated by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. RESULTS: Serum NO (189.9 +/- 49.7 microM) was significantly higher (p < 0.0028) in IA patients than in controls (131.1 +/- 18.5 microM) or patients with OA (126.9 +/- 37.1 microM). IA patients with severe inflammation had highest levels of NO, while those with mild inflammation had normal levels of NO. RT-PCR showed that PB-MDM from IA patients with active disease co-expressed iNOS and PKC-eta. This was observed in 15 out of 16 cases. All other groups with normal plasma NO expressed neither gene. CONCLUSION: Our findings show that elevated plasma NO levels were only present in IA patients with severe disease activity. We show for the first time a positive correlation between PKC-eta and iNOS expression in arthritis, supporting our earlier in vitro findings that PKC-eta expression was essential for lipopolysaccharide-mediated iNOS induction and NO production in human monocytes. PKC-eta may be important for the development of IA-induced iNOS positive phenotype in human PB-MDM.
12428439 [Therapeutic use of "biologics" in inflammatory joint and spinal diseases]. 2002 Oct At present, two principles of biologic treatment for rheumatoid arthritis and other chronic inflammatory joint and spine diseases (juvenile polyarticular idiopathic arthritis, spondarthritides) are available for use in clinical practice. These are the TNF-alpha antagonists etanercept and infliximab as well as the human recombinant IL-1 receptor antagonist anakinra. All three biologics have significant short and long-term therapeutic effects on clinical and humoral inflammatory activity compared to placebo treatment in controlled clinical trials and even radiological progression of rheumatoid arthritis can be with halted. Principally, safety and tolerability of TNF- and IL-1 antagonist are good. However, local skin reactions at injection sites and infections of the upper respiratory tract and urinary tract have to be considered. Severe infections are rare except for an increased frequency of tuberculous infection observed with infliximab worldwide. The induction of autoantibodies including antibodies to double-stranded DNA and neuralizing antibodies to etanercept and infliximab themselves can occur though their clinical significance is still upon debate. It is important to notice that the advantages of the use of biologics in individual patients has carefully to be balanced against their high costs and the increased risk of infectious side effects. Therefore, guidelines of international experts recommend the clinical use of biologics mostly for patients resistant or intolerable to conventional treatment.
12856138 Ileum-targeted steroid therapy in rheumatoid arthritis: double-blind, placebo-controlled t 2003 Jul In order to determine whether budesonide, which is believed to exert most of its anti-inflammatory effects in the intestinal tract, has a beneficial effect on disease activity in rheumatoid arthritis (RA), we treated 26 patients with active RA in double-blind fashion with either controlled ileal-release budesonide (9 mg by mouth) ( n=14) or placebo ( n=12). All patients remained on their existing disease-modifying antirheumatic drugs (DMARDs) and nonsteroidal anti-inflammatory drugs (NSAIDs). Paracetamol was used for escape analgesia. Evaluations were performed at 0, 2, and 4 weeks and included tender and swollen joint counts, duration of morning stiffness, visual analogue scale for pain (VAS) on a 100-mm horizontal scale, grip strength using a vigorimeter (lb/in(2)), haemoglobin, erythrocyte sedimentation rate (ESR) (Westergren method, mm/1st h), plasma viscosity (PV) in cP (normal range 1.5-1.72), C-reactive protein (CRP) (normal upper level 1 mg/dl), random plasma cortisol (nmol/l) drawn between 10 a.m. and 2 p.m., and blood pressure. Disease activity scores based on 28 joints (DAS 28) were also derived at all time points. Within-group comparisons revealed significant improvement in the budesonide-treated but not the placebo group with respect to numbers of tender and swollen joints, duration of morning stiffness, grip strength, pain, ESR, PV, and DAS 28. Between-group comparisons showed significant differences for ESR, PV, pain, and random plasma cortisol (drawn between 10 a.m. and 2 p.m.). There were no significant side effects in either group.
12510366 [Adalimumab]. 2002 Dec Recently, the anti-tumor necrosis factor(TNF)-alpha treatments for RA are successful in alleviating the discomforts associated with swollen, painful joints. Adalimumab(D2E7) is the first fully human anti-TNF-alpha monoclonal antibody(IgG1). Therefore, it has low immunogenicity and possibly greater therapeutic potential compared with other anti-TNF-alpha antibodies. This is administered subcutaneously at a dose of 1 mg/kg biweekly. The combined therapy with methotrexate(MTX) is efficacious to the patients who receive MTX alone and are insufficient to control symptoms of RA. The therapeutic effects become evident within 24 hours to one week after administration and reached maximum effect after one to two weeks. In adalimumab recipient, radiographic progression is also controlled and serum levels of matrix metalloproteinase-1(MMP-1) and MMP-3 decrease. For patients with RA, the treatment of adalimumab will set a new standard for symptom control and joint protection.
14994383 Polymorphism in promoter region of IL10 gene is associated with rheumatoid arthritis in wo 2004 Mar OBJECTIVE: Rheumatoid arthritis (RA) is a genetically complex disease with many possible phenotypes. We investigated IL10 and TNFA gene polymorphisms in a group of Swedish women and men with RA compared with healthy individuals to estimate combinations of alleles specific for the disease. METHODS: We analyzed 264 patients with RA and 286 healthy controls for biallelic single-nucleotide polymorphisms in the -308 position of the TNFA and in the -1087 position of the IL10 gene by polymerase chain reaction with restriction endonuclease mapping. RESULTS: The frequencies of the -308 TNFA genotypes were not different in women and men with RA in comparison to the controls. In contrast, frequencies of the GG, AG, and AA -1087 IL10 genotypes were significantly different in women in the investigated groups: 26%, 58%, and 15% for RA patients and 24%, 54%, and 28% for the controls (chi-square = 8.18, p < 0.02). We confirmed this finding in a separate dataset of female patients and controls. The frequencies of the IL10 genotypes in men were similar in the patients and controls. We found no differences in the distribution of the TNFA or IL10 genotypes in relation to rheumatoid factor in the patients. CONCLUSION: On the basis of IL10 polymorphism, female patients with RA seem to represent a separate disease subgroup.
12139377 Serum IL-12 in systemic lupus erythematosus: absence of p70 heterodimers but presence of p 2002 Biologically active IL-12 is a 70 kDa heterodimeric cytokine (IL-12 p70) mainly produced by antigen-presenting cells (APC) and made of disulfide-linked alpha (p35) and beta (p40) chains. Since the production of the p40 subunit is independently regulated from that of IL-12 p70, we compared levels of p40 and IL-12 p70 in the sera of patients with systemic lupus erythematosus (SLE). Sera obtained from rheumatoid arthritis (RA) patients and healthy subjects were used as controls. Serum p40 titers were significantly higher in SLE patients (mean +/- s.e.m.: 348 +/- 40 pg/ml) compared with patients with rheumatoid arthiritis (mean +/- s.e.m.: 116 +/- 18 pg/ml, P < 0.0001) or controls (mean +/- s.e.m.: 0 +/- pg/ml, P < 0.0001). By contrast, IL-12 p70 was not detected in any serum. In SLE patients, serum p40 levels were positively correlated with the SLEDAI (r = + 0.56, P = 0.02) and negatively with serum C3 levels (r = - 0.42, P = 0.03). Follow-up measurements indicated that serum p40 dropped significantly after immunosuppressive therapy. Finally, size exclusion chromatography with p40 immunoprecipitates obtained from SLE sera demonstrated that p40 was present as a monomer, and not as a homodimer, nor as a p19/p40 (IL-23) heterodimer. In conclusion, serum p40 monomers (but not IL-12 p70 titers) are elevated in the sera of SLE patients commensurate with disease activity. While the relevance of these observations needs to be further investigated, our results are consistent with the APC dysfunction described in SLE.