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ID PMID Title PublicationDate abstract
23480220 Mechanisms of the joint-protective effects of p38 MAPK inhibitors in rodent arthritis. 2008 Feb BACKGROUND: The p38 kinases (p38) are proline-directed serine/threonine enzymes of the mitogen-activated protein kinase family. Although p38 participates in signaling cascades leading to joint destruction in rheumatoid arthritis (RA), the mechanisms of its actions in this process are not completely understood. OBJECTIVE: Elucidating the joint-protective mechanisms of p38 inhibitors in rodent models of RA may have implications in the design of p38-based therapies for this disease. METHOD: This review highlights the tissue- and cell-specific complex interactions between p38 and pro-inflammatory cytokines. CONCLUSION: This review provides evidence that p38α and TNF-α are key partners in RA, and that inhibition of this kinase should be effective in treating this disease.
19038581 IL-14 alpha, the nexus for primary Sjögren's disease in mice and humans. 2009 Mar To evaluate the role of interleukin 14 alpha (IL-14a) in Sjögren's syndrome (SS), we evaluated the expression of IL-14a in the peripheral blood lymphocytes (PBL) of patients with primary and secondary SS and normal controls by quantitative RT-PCR. In addition, transgenic IL-14a mice were analyzed from 6 weeks of age to death for both histological and immunological features of Sjögren's disease. Patients with both primary and secondary Sjögren's syndrome expressed IL-14a at statistically higher levels in their peripheral blood compared to normal controls matched for age, sex and ethnic group. Transgenic mice in which IL-14a expression was increased constitutively were previously demonstrated to develop hypergammaglobulinemia, autoantibodies, infiltration of the parotid glands with lymphocytes, mild immune-complex mediated renal disease and large B cell lymphoma. In this paper we expand these observations to demonstrate that these mice develop all the clinical and immunological features of primary Sjögren's disease in the same relative time frame as patients with primary Sjögren's disease: stage 1-early hypergammaglobulinemia and autoantibody production, stage 2-decreased salivary gland function with early lymphocytic infiltration of the submandibular glands only, but antibody deposition in the submandibular and parotid glands, stage 3-lymphocytic infiltration of the submandibular, parotid and lacrimal glands with B and T lymphocytes and plasma cells along with interstitial lung disease and mild renal disease, and stage 4-large B cell lymphoma. Thus IL-14a is important in the pathophysiology of Sjögren's disease. The IL-14a transgenic mouse is a novel animal model that can be utilized to understand the pathophysiology of Sjögren's disease.
17959073 [Expression of forkhead box protein P3 in peripheral blood and salivary gland of patients 2007 Jul OBJECTIVE: To investigate the expression of forkhead box protein P3 (Foxp3) in the peripheral blood and salivary gland of patients with Sjogren's Syndrome (SS). METHODS: Reverse transcription polymerase chain reaction (RT-PCR) was used to examine Foxp3mRNA expression in the CD(4)(+) T cells and the salivary glands from 6 primary SS patients and 6 normal controls. Serial sections of biopsied salivary gland (SG) were examined with immunohistochemistry, using monoclonal mouse anti-human CD(4) and Foxp3 in 6 healthy controls and 31 primary SS patients. RESULTS: Significant difference in the number of infiltrating CD(4)(+) T cells was noted in the salivary glands of the patients and controls, but Foxp3(+)CD(4)(+) T cells were almost absent in those biopsy samples. Foxp3mRNA expression in the blood of SS patients was significantly lower than that in normal controls (0.21 +/- 0.17 vs 1.32 +/- 0.38, P < 0.0184). Foxp3mRNA expression was not detectable in the tissue of the salivary glands (n = 6). CONCLUSION: The absence of Foxp3(+)CD(4)(+) T cells in salivary glands with reduction of Foxp3mRNA expression in peripheral blood suggests an important role of Foxp3 in the pathogenesis of SS.
17938903 Identification of a quantitative trait locus regulating B cell-dominant infiltration into 2007 Nov Sjögren's syndrome (SS) is caused by an autoimmune sialodacryoadenitis, and up to 5% of patients with SS develop malignant B cell growth. The IQI mouse is a spontaneous model of primary SS in which B cells are the dominant cellular subpopulation among mononuclear infiltrates in sialitis lesions. Understanding the genetic control of aberrant B cell growth in IQI mice may help elucidate the genetic mechanisms involved in B-lineage hyperplasia leading to malignant transformation in human SS. B cell-dominant infiltration in the submandibular glands of 6-month-old IQI and C57BL/6 (B6) mice and their F1 and F2 progenies was quantified as B-lymphocytic sialitis score, and a genome-wide scan of 179 (IQI x B6) F2 females was performed to identify a quantitative trait locus (QTL) controlling this phenotype. A QTL significantly associated with variance in B-lymphocytic sialitis score was mapped to the D6Mit138 marker (position of 0.68cM) on proximal chromosome 6, with a logarithm of odds score of 4.3 (p = 0.00005). This QTL, named autoimmune sialitis in IQI mice, associated locus 1 (Asq1), colocalized with Islet cell autoantigen 1 (Ica1), which encodes a target protein of the immune processes that define the pathogenesis of primary SS in humans and in the nonobese diabetic mouse model.
17205841 Oral and dental aspects of Sjögren's syndrome. 2006 Winter Sjögren's syndrome is a common condition which can result in significant physical and emotional debility. Dentists can play a pivotal role in the prompt diagnosis, investigation and management of patients with Sjögren's syndrome. A sound understanding of the pathogenesis, presentation and current management of Sjögren's syndrome, will enable the general dental practitioner to make a significant contribution to the oral health and general well-being of those affected by the disease. This article aims to provide the general dental practitioner with a comprehensive and practical guide to current developments and best practise in the care of these individuals.
17718306 Understanding monoclonal antibodies. 2007 Jul Elsewhere in this issue, we review new treatments for neovascular age-related macular degeneration, of which, bevacizumab and ranibizumab are monoclonal antibodies. These are two of a growing number of monoclonal antibodies currently available for therapeutic use in the UK. We have reviewed some of the others before: bevacizumab and cetuximab for colorectal cancer; infliximab for rheumatoid arthritis; omalizumab for severe asthma; and trastuzumab for breast cancer. The expanding range of these products and their clinical applications can make it difficult to keep abreast of developments in this field. With this in mind, we describe the key principles underlying the production, use and naming of monoclonal antibodies.
18638686 Complementary treatments in rheumatic diseases. 2008 May Which complementary therapies are effective for reducing pain in which rheumatic conditions? This is the question this article addresses, with particular emphasis on treatments that are, according to the totality of the available trial data, likely to be effective, and with a focus on six conditions relevant to rheumatologists: back pain, fibromyalgia, myofascial pain, neck pain, osteoarthritis, and rheumatoid arthritis.
18176391 [Follicular bronchiolitis]. 2007 Nov INTRODUCTION: Follicular bronchiolitis (FB) is a rare type of cellular bronchiolitis characterised by the presence of hyperplastic lymphoid follicles with reactive germinal centres, distributed along the bronchovascular bundles. OBSERVATION: A non-smoking 36 year old woman was seen because of progressive exertional dyspnoea for 2 years. Chest x-ray and lung CT scan were normal. Pulmonary function tests revealed irreversible airflow obstruction. Exercise testing showed a ventilatory limitation of aerobic capacity with limitation of volume recruitment. The diagnosis of FB was obtained by surgical biopsy. A deficiency of immunoglobulins G4 and M was found. CONCLUSION: The main clinical manifestation of FB is exertional dyspnoea in a young patient. The lung CT scan frequently shows peripheral micronodules but a normal scan does not exclude the diagnosis. The main causes of FB are collagen vascular diseases (especially rheumatoid arthritis) and immunodeficiency syndromes. The treatment of FB is not well defined.
18081542 Infliximab in dermatological treatment: beyond psoriasis. 2008 Jan Infliximab is a chimeric monoclonal antibody of the IgG1 class. Experience from its use has been accumulated in rheumatology and gastroenterology by the treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and inflammatory bowel disease, respectively. Because of its TNF-alpha binding capacity it has been approved for the treatment of moderate-to-severe plaque psoriasis. Moreover, it has also been evaluated in other inflammatory dermatoses as well as systemic diseases involving the skin such as severe atopic dermatitis, pityriasis rubra pilaris, pyoderma gangrenosum and cutaneous sarcoidosis. The possible future uses of infliximab in dermatology are being reviewed herein.
20476905 Anakinra in the treatment of rheumatic disease. 2006 May Anakinra is a specific receptor antagonist of interleukin-1 that differs from naturally occurring interleukin-1 receptor antagonist by the presence of a methionine group. It is administered by daily subcutaneous injection. Anakinra improves the clinical signs and symptoms of rheumatoid arthritis, slows radiographic progression and improves patient physical function. The most common adverse event is an injection site reaction. Anakinra has been associated with an increased incidence of serious infections and has an increased standardized incidence ratio for lymphoma. It has not been found to be associated with the development of opportunistic infections, worsening of congestive heart failure or the development of demyelinating disease. It appears to be effective in treating adult Stills disease, systemic-onset juvenile idiopathic arthritis and chronic infantile neurological cutaneous and articular syndrome (also known as neonatal-onset multisystem inflammatory disease syndrome).
20477078 New insights into eicosanoid biosynthetic pathways: implications for arthritis. 2006 Mar Eicosanoid is a collective term for the family of lipid mediators derived from arachidonic acid (AA) metabolism. This complex family of lipids is comprised of prostaglandins, thromboxanes, leukotrienes, hydroxyeicosatetraenoic acids (HETEs) and lipoxins (LXs). The most studied enzymatic pathway for AA metabolism proceeds via cyclooxygenase (COX). However, AA can also be metabolized by the lipoxygenases (LOXs) to LTs and HETEs, and recent studies have demonstrated a unique AA metabolic pathway mediated by both COX and LOX. Eicosanoids are also implicated as important mediators of several chronic inflammatory diseases, including rheumatoid arthritis (RA) and osteoarthritis (OA). Current therapies to treat RA and OA symptoms are directed toward the inhibition of enzymes and mediators generated within the eicosanoid pathway. This review will give insights into the current understanding of the eicosanoid biosynthetic pathway and its role in the RA and OA disease states. In addition, current therapies and future therapeutic targets within the eicosanoid pathway for the treatment of RA and OA will be discussed.
18493620 Pharmacological inhibition of nicotinamide phosphoribosyltransferase/visfatin enzymatic ac 2008 May 21 Nicotinamide phosphoribosyltransferase (NAMPT), also known as visfatin, is the rate-limiting enzyme in the salvage pathway of NAD biosynthesis from nicotinamide. Since its expression is upregulated during inflammation, NAMPT represents a novel clinical biomarker in acute lung injury, rheumatoid arthritis, and Crohn's disease. However, its role in disease progression remains unknown. We report here that NAMPT is a key player in inflammatory arthritis. Increased expression of NAMPT was confirmed in mice with collagen-induced arthritis, both in serum and in the arthritic paw. Importantly, a specific competitive inhibitor of NAMPT effectively reduced arthritis severity with comparable activity to etanercept, and decreased pro-inflammatory cytokine secretion in affected joints. Moreover, NAMPT inhibition reduced intracellular NAD concentration in inflammatory cells and circulating TNFalpha levels during endotoxemia in mice. In vitro pharmacological inhibition of NAMPT reduced the intracellular concentration of NAD and pro-inflammatory cytokine secretion by inflammatory cells. Thus, NAMPT links NAD metabolism to inflammatory cytokine secretion by leukocytes, and its inhibition might therefore have therapeutic efficacy in immune-mediated inflammatory disorders.
18163482 Amphipathic weak acid glucocorticoid prodrugs remote-loaded into sterically stabilized nan 2008 Jan OBJECTIVE: The use of glucocorticoids (GCs) in rheumatoid arthritis is limited by side effects related to unfavorable pharmacokinetics and biodistribution. Liposomal GC formulations have been studied since the 1970s in an attempt to overcome this obstacle, but none has entered clinical use. We undertook this study to determine whether a novel approach could overcome the limitations that have thus far prevented the clinical use of these formulations: low drug:lipid ratio, low encapsulation efficiency, and lack of controlled release. METHODS: We used approximately 80-nm sterically stabilized (pegylated) nanoliposomes (NSSLs), which were remote-loaded with an amphipathic weak acid GC (such as methyl prednisolone hemisuccinate) utilizing an intraliposome (aqueous compartment)-high/extraliposome (bulk medium)-low transmembrane calcium acetate gradient. This unique method actually "traps" the GC in the liposomal aqueous phase as a calcium-GC precipitate. RESULTS: Our liposome formulation exhibited high encapsulation efficiency (94%) and a high drug:lipid mole ratio (0.41) and demonstrated controlled release of the encapsulated GC during systemic circulation and in inflamed paws in rats with adjuvant-induced arthritis. In addition, both in arthritic rats and in a Beagle dog, we showed the pharmacokinetic advantage of using liposomes as GC carriers. Finally, we demonstrated the superior therapeutic efficacy of our liposome formulation over that of free GCs in arthritic rats, both in early and in peak disease stages. CONCLUSION: Amphipathic weak acid GCs remote-loaded into approximately 80-nm NSSLs overcome past limitations of liposomal GC formulations. The unique loading method, which also leads to controlled release, improves the therapeutic effect both systemically and locally. Such a development has great potential for improving GC therapy.
17472572 Targeting TNF-alpha with a tetravalent mini-antibody TNF-TeAb. 2007 Sep 1 Anti-TNF-alpha [anti-(tumour necrosis factor-alpha)] therapy is widely considered to be among the most efficient treatments available for rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease. In the present study a tetravalent mini-antibody, named 'TNF-TeAb', was constructed by fusing the tetramerization domain of human p53 to the C-terminus of an anti-TNF-scFv [anti-(TNF-alpha-single-chain variable fragment)] via a long and flexible linking peptide derived from human serum albumin. TNF-TeAb was overexpressed as inclusion bodies in the cytoplasm of Escherichia coli, purified to homogeneity by immobilized- metal affinity chromtaography under denaturing conditions and produced in functional form by using an in vitro refolding system. In vitro bioactivity assays suggested that tetramerization of TNF-scFv resulted in an enormous gain in avidity, which endowed TNF-TeAb with a stronger ability to inhibit both receptor binding and cytolytic activity of TNF-alpha. TNF-alpha targeting therapy in rats with collagen-induced arthritis demonstrated that TNF-TeAb provided a much more significant therapeutic effect than did TNF-scFv in suppressing arthritis progression, attenuating inflammation and destruction in joints, and down-regulating pro-inflammatory cytokines and anti-(type II collagen) antibody. The conclusions are therefore (i) that multimerization of the antibody fragment by a self-association peptide is an efficient way to increase its avidity and (ii) that TNF-TeAb has potential applicability for anti-TNF-alpha therapy.
18464303 Bone protective effect of simvastatin in experimental arthritis. 2008 Jun OBJECTIVE: Emerging evidence suggests that clinically important antiinflammatory effects of HMG-CoA reductase inhibition may extend beyond cardiovascular disease to other inflammatory disorders, such as rheumatoid arthritis (RA). Protective bone-specific anabolic and antiresorptive effects of HMG-CoA reductase inhibitors have also been evaluated in normal and osteoporotic bone. The specific effect of statins on inflammation-induced bone loss has not previously been a focus of evaluation. We investigated whether simvastatin, a potent HMG-CoA reductase inhibitor, alters bone turnover in an animal model of RA, thus preventing periarticular bone loss. METHODS: Hydrolyzed simvastatin (20 mg/kg/day) was administered subcutaneously to female Lewis rats 4 days before or 8 days after induction of arthritis by intraperitoneal injection of streptococcal cell wall or vehicle. Effects of simvastatin (vs vehicle) on periarticular bone, assessed by bone mineral density (BMD), biochemical markers of bone turnover, and joint histology, were determined. Effects on joint swelling were assessed clinically and histologically. RESULTS: Simvastatin prevented early and late joint inflammation in association with a decrease in articular macrophage influx. Simvastatin suppressed the periarticular bone destruction occurring late in the course of disease, preserving periarticular BMD and preventing increases in periarticular osteoclasts and serum pyridinoline levels in arthritic animals, while having no effect on these measures in normal animals. Osteocalcin levels, which were decreased in arthritic animals, were unaltered by statin treatment. CONCLUSION: Our results suggest that inhibition of HMG-CoA reductase may be therapeutically useful in preserving periarticular bone in RA joints via suppression of inflammation-induced bone resorption.
17083618 Strain differences and the role for HSP47 and HSP70 in adjuvant arthritis in rats. 2006 Dec Because of high sequence homology between microbial and endogenous heat shock proteins (HSP), immunological cross-reactivity to microbial HSP has been suggested as a possible cause of the development of autoimmune diseases, such as rheumatoid arthritis. The present study aimed to determine a potential role of HSP47, a molecular chaperone involved in the synthesis and assembly of collagen molecules, and microbial HSP71 (mHSP71) in adjuvant arthritis (AA) in two rat strains: Dark Agouti (DA), susceptible to AA induction and Albino Oxford (AO), which is resistant to AA induction. Immunization with complete Freund's adjuvant (CFA) induced an increased expression of HSP47 in joints of DA rats, which exhibited severe clinical signs of AA at the time of disease peak, while this protein was not detectable in joints of AO rats. In contrast, no strain differences in HSP72 (rat analogue of mHSP71) expressions in joints were observed. The increased levels of anti-HSP47 antibodies were detected in sera of DA rats during the AA peak, while the immunization with CFA increased levels of anti-mHSP71 antibodies in sera of AO rats. HSP47 and mHSP71 reduced proliferation of draining inguinal lymph node cells (LNC) in resistant AO rat strain, leading to a hypothesis that both HSP participated in AA control. Finally, mHSP71 potentiated the apoptotic response of LNC in susceptible DA rat strain. In conclusion, our findings indicate involvement of HSP47 in the development of AA in the rat, and point out to the regulatory role for both HSP47 and mHSP71.
17944452 Probing molecular interactions within class II MHC Aq/glycopeptide/T-cell receptor complex 2007 Nov 15 T cells obtained in a mouse model for rheumatoid arthritis are activated by a glycopeptide fragment from rat type II collagen (CII) bound to the class II major histocompatibility complex Aq molecule. We report a comparative model of Aq in complex with the glycopeptide CII260-267. This model was used in a structure-based design approach where the amide bond between Ala261 and Gly262 in the glycopeptide was selected for replacement with psi[COCH2], psi[CH2NH2+], and psi[(E)-CH=CH] isosteres. Ala-Gly isostere building blocks were then synthesized and introduced in CII260-267 and CII259-273 glycopeptides. The modified glycopeptides were evaluated for binding to the Aq molecule, and the results were interpreted in view of the Aq/glycopeptide model. Moreover, recognition by a panel of T-cell hybridomas revealed high sensitivity for the backbone modifications. These studies contribute to the understanding of the interactions in the ternary Aq/glycopeptide/T-cell receptor complexes that activate T cells in autoimmune arthritis and suggest possibilities for new vaccination approaches.
17537462 Low frequency and low intensity pulsed electromagnetic field exerts its antiinflammatory e 2007 Jun 6 Rheumatoid arthritis (RA) is a chronic inflammatory disorder affecting 1% of the population worldwide. Pulsed electromagnetic field (PEMF) has a number of well-documented physiological effects on cells and tissues including antiinflammatory effect. This study aims to explore the antiinflammatory effect of PEMF and its possible mechanism of action in amelioration of adjuvant induced arthritis (AIA). Arthritis was induced by a single intradermal injection of heat killed Mycobacterium tuberculosis at a concentration of 500 microg in 0.1 ml of paraffin oil into the right hind paw of rats. The arthritic animals showed a biphasic response regarding changes in the paw edema volume. During the chronic phase of the disease, arthritic animals showed an elevated level of lipid peroxides and depletion of antioxidant enzymes with significant radiological and histological changes. Besides, plasma membrane Ca(2+) ATPase (PMCA) activity was inhibited while intracellular Ca(2+) level as well as prostaglandin E(2) levels was noticed to be elevated in blood lymphocytes of arthritic rats. Exposure of arthritic rats to PEMF at 5 Hzx4 microT x 90 min, produced significant antiexudative effect resulting in the restoration of the altered parameters. The antiinflammatory effect could be partially mediated through the stabilizing action of PEMF on membranes as reflected by the restoration of PMCA and intracellular Ca(2+) levels in blood lymphocytes subsequently inhibiting PGE(2) biosynthesis. The results of this study indicated that PEMF could be developed as a potential therapy for RA in human beings.
17322385 Calcitonin and prednisolone display antagonistic actions on bone and have synergistic effe 2007 Mar We tested here the hypothesis that calcitonin and glucocorticoids, known to modulate bone metabolism, could have opposite actions on bone cells regulating expression of cytokine receptor activator of nuclear factor-kappaBeta ligand (RANKL) and osteoprotegerin (OPG). In the U2OS osteosarcoma cell line, calcitonin (10(-11) to 10(-9) mol/L) reduced RANKL and augmented OPG both at the mRNA and protein levels. Cell incubation with prednisolone (10(-8) to 10(-6) mol/L), the glucocorticoid chosen for this study, produced opposite results. These molecular studies prompted more functional analyses whereby osteoclast bone resorptive activity was determined. Calcitonin (10(-10) mol/L) abrogated the stimulating effect of 10 ng/ml RANKL or 10(-9) mol/L prednisolone; similar results were obtained with OPG. Assessment of calcitonin and prednisolone effects in an in vivo model of rheumatoid arthritis revealed partially surprising results. In fact, calcitonin not only preserved bone morphology (as assessed on day 18) in rats subjected to arthritis and treated with prednisolone (0.8 to 4 mg/kg daily from day 13) but also synergized with the steroid to elicit its antiarthritic effects. These results suggest that calcitonin could be used as a novel cotreatment to augment efficacy and reduce side effects associated with the prolonged use of steroids.
17965117 Distribution and clinical significance of blood dendritic cells in children with juvenile 2008 Jun BACKGROUND: A role for dendritic cells (DC) in the development of adult rheumatoid arthritis has been suggested. To date, this problem has been poorly explored in juvenile idiopathic arthritis (JIA). OBJECTIVE: To analyse distribution and maturation status of blood DC (BDC) in JIA. METHODS: Absolute BDC counts were assessed by the "single platform" method in peripheral blood (PB) of 47 untreated children with JIA and 32 healthy controls. Moreover, BDC were investigated in JIA synovial fluid (SF). When the panel of monoclonal antibodies against BDC antigens (BDCA) was used, three BDC subpopulations were determined: myeloid type 1 (mDC1; BDCA-1+/HLA-DR+/CD19-), myeloid type 2 (mDC2; BDCA-3+/HLA-DR+/CD14-) and plasmacytoid (pDC; BDCA-2+/HLA-DR+/CD123+). RESULTS: A considerable deficiency of all subtypes of BDC was found in the PB of children with JIA. BDC counts in JIA SF were significantly higher than in PB both from children with JIA (p<0.001) and healthy children (p<0.001). SF BDC, especially mDC1 and mDC2 subtypes, had significantly higher expression of maturation markers (CD40, CD80, CD86 or CD83 antigens) than those from PB. A smaller number of PB BDC at diagnosis correlated significantly with poor response to treatment. CONCLUSIONS: A deficiency of BDC in PB is accompanied by enrichment of SF with those cells. Probably, circulating BDC migrate to joints where they undergo maturation and help to mediate and maintain the local immune response. Interestingly, the level of PD BDC deficiency seems to influence the outcome in children with JIA.