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ID PMID Title PublicationDate abstract
17172718 Novel opportunities for therapeutic targeting in systemic autoimmune diseases. 2007 Systemic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, continue to cause significant morbidity in affected persons. In the past few years, significant progress was made in understanding their pathogenesis and the underlying molecular mechanisms. As a result, a number of new exciting therapeutic options have become available, and novel therapeutic targets have emerged, including B-cell depletion therapies, B cell-activating factor of tumor necrosis factor family (BAFF) antagonists, and FcgammaRIIB receptor antagonists. Also promising is the current interest centered on the development of inhibition of signal transduction pathways, such as pharmacological inhibitors that act at various levels of signal transduction pathways.
17172663 Development of transfection and high-producer screening protocols for the CHOK1SV cell sys 2006 Oct To date, the FDA has approved 18 monoclonal antibody (MAb) therapeutic drugs with targets ranging from asthma and rheumatoid arthritis to leukemia. Many of these approved products are produced in Chinese hamster ovary cells (CHO) making CHO a significant and relevant host system. We studied the applicability of CHOK1SV cells as a potential host cell line for MAb production in terms of timelines, achievable titers, transfectant stability, and reproducibility. CHOK1SV, developed by Lonza Biologics, is a suspension, protein-free-adapted CHOK1-derivative utilizing the glutamine synthetase (GS) gene expression system. CHOK1SV expresses the GS enzyme endogenously; thus, positive transfectants were obtained under the dual selection of methionine sulfoximine (MSX) and glutamine-free media. We examined outgrowth efficiencies, specific productivities, and achievable batch titers of three different IgG MAbs transfected into CHOK1SV. Reducing the MSX concentration in the initial selection medium resulted in a decreased incubation time required for transfectant colonies to appear. Specific productivities of "high-producers" ranged between 11 and 49 pg/c/d with batch titers ranging from 105 to 519 mg/L. Transfectant stability and the effects of MSX also were investigated, which indicated that the addition of MSX was necessary to maintain stable MAb production. Cell growth was stable regardless of MSX concentration.
16995741 A preliminary in silico lead series of 2-phthalimidinoglutaric acid analogues designed as 2006 Sep Matrix metalloproteinases (MMPs) have been the subject of intense research because of their roles in tumor metastasis and in the rise and spread of degenerative diseases such as osteo- and rheumatoid arthritis. A preliminary class of 140 druglike, small-molecule matrix metalloproteinase-3 inhibitors, intended as starting scaffolds for optimization and synthesis, has been designed in silico using a series of highly predictive three-dimensional quantitative structure-activity relationship models, including comparative molecular field analysis and comparative molecular similarity indices analysis, with docking and scoring. Thalidomide was chosen as the skeleton on which to base the new lead series, as it moderately inhibits MMP-3, is antiangiogenic, and lends itself easily to structural modifications. Most of the new compounds demonstrate medium to high predicted biological activity and good bioavailability as estimated by the octanol-water partition coefficient ClogP. Compound 102 in particular exhibits extremely favorable predicted activity against MMP-3; is moderately bioavailable; satisfies Lipinski's Rule of Five; and shows promise for further optimization, synthesis, and experimental evaluation as a potential adjunct anticancer or antirheumatic therapeutic.
16969593 The pathogenesis, epidemiology and management of glucocorticoid-induced osteoporosis. 2006 Sep Oral glucocorticoids (GCs) are frequently used in the treatment of inflammatory conditions, such as rheumatoid arthritis or asthma. They have adverse skeletal effects, primarily through reductions in bone formation and osteocyte apoptosis. Several findings indicate that changes in the quality of bone may significantly contribute to the increased risk of fracture and that loss of BMD only partially explains the increased risk of fracture in oral GC users. Epidemiological studies have found that the increases in the risk of fracture in oral GC users are dose dependent and occur within three months of starting GC therapy. Daily doses of >2.5 mg prednisone equivalent have been associated with increases in the risk of fractures and randomised studies reported adverse skeletal effects with daily doses as low as 5 mg. After discontinuation of GC treatment, the risk of fracture may reduce towards baseline levels unless patients previously used high cumulative doses of oral GCs. Users of inhaled GCs have also an increased risk of fracture, especially at higher doses. But it is likely that this excess risk is related to the severity of the underlying respiratory disease, rather than to the inhaled GC therapy. It has been recommended that patients who start on oral GC therapy should receive calcium and vitamin D supplementation. Patients with a higher risk of fracture should also receive a bisphosphonate.
16887960 CCR5 in T cell-mediated liver diseases: what's going on? 2006 Aug 15 The chemokine receptor CCR5 came into worldwide prominence a decade ago when it was identified as one of the major coreceptors for HIV infectivity. However, subsequent studies suggested an important modulatory role for CCR5 in the inflammatory response. Specifically, CCR5 has been reported to directly regulate T cell function in autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and type 1 diabetes. Moreover, T cell-mediated immune responses are proposed to be critical in the pathogenesis of autoimmune and viral liver diseases, and recent clinical and experimental studies have also implicated CCR5 in the pathogenesis of autoimmune and viral liver diseases. Therefore, in this brief review, we highlight the evidence that supports an important role of CCR5 in the pathophysiology of T cell-mediated liver diseases with specific emphasis on autoimmune and viral liver diseases.
16868019 A non-major histocompatibility locus determines tissue specificity in the pathogenic proce 2007 Feb BACKGROUND: The incidence and characteristics of spontaneous ankylosis in the ankle of specific F(1) mice descended from two Fas-deficient strains were reported. Here the coincidence of synovial proliferation and ankylosis in the descendent F(2) mice is reported. AIM: To clarify whether the two distinct manifestations are genetically different. METHODS: An arthropathic group of mice (MCF(2)) were bred by intercrossing MRL/Mp.Fas(lpr)-sap(-)/sap(-) and C3H/He.Fas(lpr) mice. All mice were killed by bleeding under anaesthesia when they were 6 months old. Pathological grades for synovial proliferation were determined by microscopical examination. To obtain a linkage locus, the whole genome of male MCF(2) mice was scanned by using 73 microsatellite markers. RESULTS: Synovial proliferation was equally observed in male and female MCF(2) mice. No correlation was observed between the grades of synovial proliferation and the ankylosis occurring in the MCF(2) mice. A suggestive susceptibility locus was shown in the middle of chromosome 11. This locus was an MRL allele with a recessive inheritance mode. CONCLUSION: The pathogenic mechanisms of synovial proliferation and ankylosis are genetically different. The present locus is overlapped with some loci associated with rheumatoid arthritis and with others associated with experimental arthritides.
16831655 Fracture and nonunion of the olecranon in total elbow arthroplasty. 2006 Jul BACKGROUND: While fracture and nonunion of the olecranon have been reported in patients undergoing total elbow arthroplasty, little information exists about the management and outcome of these cases. METHODS: Twenty-four patients (twenty-five elbows) were studied; fifteen (sixteen elbows) with rheumatoid arthritis and nine with post-traumatic elbow disorders. Twenty-three of the twenty-five elbows presented with an olecranon fracture or nonunion prior to the reported arthroplasty. During arthroplasty the olecranon fragment was initially treated by tension band in sixteen elbows, excision in four, suture fixation in two and three with stable fibrous union were left alone. RESULTS: At an average follow-up of 66 months (range, 18 to 242), there were twelve excellent, nine good, three fair and one poor results. The mean pre-operative Mayo Elbow Performance Score improved from 42 (range, 20 to 62) points pre-operatively to 86 (range, 50 to 100) points post-operatively (p < 0.001). Of the eighteen patients undergoing an attempt at union, nine (50%) obtained osseous union, eight (45%) developed a stable fibrous union and one patient underwent subsequent excision of the fragment due a superficial infection (5%). Fifteen of twenty-one could extend the hand above the head against gravity. CONCLUSION: A functional arc of motion and satisfactory clinical outcome can be achieved with osseous or a stable fibrous nonunion.
16829988 [HAQ-DI Italian version in systemic sclerosis]. 2006 Apr OBJECTIVE: To investigate the Italian version of HAQ-DI (Health Assessment Questionnaire Disability Index) in systemic sclerosis (SSc). METHODS: 121 SSc patients, satisfying ACR criteria for the classification of this disease and consecutively admitted to a tertiary Unit, were invited to participate to the study. The Italian version of HAQ-DI, as validated in rheumatoid arthritis, was administered to each of them. The relationships between this parameter and the following disease aspects: disease subset, wide extent of skin sclerosis, joint contractures, myopathy, active digital ulcers, were investigated. RESULTS: HAQ-DI resulted to be 0.772+/-0.074 (mean+/-SE) Statistically significant differences in HAQ-DI scores were detected between patients with and respectively without wide extent of skin sclerosis (ie modified Rodnan skin score >14) (1.158+/-0.176 vs 0.652+/-0.076; P<0.001), joints contractures (0.839+/-0.076 vs 0.159+/-0.147; P<0.001), myopathy (1.875+/-0.184 vs 0.656+/-0.071; P<0.001), digital ulcers (1.047+/-0.135 vs 0.680+/-0.109; P=0.006). CONCLUSIONS: Our data support the validity of the Italian version of HAQ-DI in SSc.
16476049 Dealing with the family: CD147 interactions with cyclophilins. 2006 Mar CD147 is a widely expressed plasma membrane protein that has been implicated in a variety of physiological and pathological activities. It is best known for its ability to function as extracellular matrix metalloproteinase inducer (hence the other name for this protein, EMMPRIN), but has also been shown to regulate lymphocyte responsiveness, monocarboxylate transporter expression and spermatogenesis. These functions reflect multiple interacting partners of CD147. Recently, interaction of CD147 with proteins of the cyclophilin family has been demonstrated and activity of CD147 as a signalling receptor to extracellular cyclophilins A and B has been shown. Given that extracellular cyclophilins are potent chemotactic agents for various immune cells, further studies of the role of cyclophilin-CD147 interaction in inflammation followed. They demonstrated that agents targeting CD147 or cyclophilin had a significant anti-inflammatory effect in animal models of acute or chronic lung diseases and rheumatoid arthritis. Here, we review the current knowledge about interactions between CD147 and cyclophilins.
16471231 [The pathogenesis of inflammatory dermatoses, especially psoriasis]. 2006 Jan 28 The skin contains a variety of cell types and mediators, which together constitute the skin's immune system and play a key role in protecting the human body against dangers from outside. Dysregulation of the skin's immune system, however, frequently occurs and can result in undesirable inflammatory processes in the skin. A typical example of an undesirable inflammation in the skin is the chronic inflammatory skin disease psoriasis. In the pathogenesis of psoriasis, both genetic and environmental factors play a key role. In psoriasis, the complex interactions between T-lymphocytes, antigen-presenting cells, keratinocytes and pro-inflammatory cytokines and chemokines are disturbed. The two most widely accepted hypotheses are: (a) psoriasis is a T-cell mediated autoimmune disease, and (b) psoriasis is the result of a too finely adjusted system for regulating inflammation in the skin. The result of both mechanisms is a chronic inflammatory reaction fuelled by pro-inflammatory type-I cytokines that lead to the psoriasis-skin phenotype. With the development ofbiologicals, it has become feasible to target specific molecules in the immune process, for example type-I cytokines and the molecules present on pathogenic T-cells. This approach has already proved successful in the treatment of rheumatoid arthritis and Crohn's disease, creating novel therapeutic options for psoriasis and other inflammatory dermatoses.
16393560 [CD4 + CD25 + regulatory T cells and their importance to human illnesses]. 2006 Jan 3 Regulatory T cells ensure a balanced immune response that is competent both to fight pathogens, at the same time, to recognize self-antigens and commensals as harmless. Regulatory mechanisms are essential in preventing autoimmune disorders but may also facilitate the progression of malignant diseases and the establishment of latent infections via suppression of the host immune response. Regulatory T cells arise in the thymus, and regulatory T cell function can be induced in the periphery, so-called infectious tolerance. An absolute or relative defect in regulatory T cell function may contribute to the development of autoimmune disorders such as rheumatoid arthritis, type 1 diabetes mellitus, multiple sclerosis and chronic inflammatory bowel disease. Regulatory T cell therapy is a tempting strategy for reestablishing the immune balance and thus preventing or reversing these disorders. Reestablishment of the immune balance may be accomplished by adoptive transfer of ex vivo-propagated regulatory T cells or by induction of regulatory functions locally in the organs, although such strategies are in their infancy in human research.
18166219 Insights into the pathology and treatment of spondyloarthritis: from the bench to the clin 2008 Oct OBJECTIVE: The spondyloarthritides are a set of chronic inflammatory diseases that consists of 5 interrelated subsets (ankylosing spondylitis [AS], psoriatic arthritis [PsA], reactive arthritis, arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthropathy). The aim of this review was to evaluate the classification, genetic susceptibility, pathology, and response to treatment of spondyloarthritis (SpA). METHODS: Searches were conducted of the PubMed database for articles focusing on the classification, pathology, and treatment of SpA. RESULTS: The 5 subsets of SpA share many clinical, immunohistochemical, and genetic features, including the common presence of human leukocyte antigen-B27 and the absence of rheumatoid factor. Evidence suggests that the pathology of SpA is mediated by immune cells. In particular, tumor necrosis factor-alpha appears to be an important driver of inflammation and damage in SpA. A number of different SpA classification criteria have been developed, including the Modified New York Criteria for AS, the European Spondyloarthropathy Study Group criteria, the Amor criteria, as well as criteria for PsA, notably the Moll and Wright criteria and the Classification of Psoriatic Arthritis criteria. Suboptimal efficacy and adverse effects often limit the use of conventional pharmacologic treatments for SpA, including nonsteroidal antiinflammatory drugs and disease-modifying antirheumatic drugs, such as methotrexate and sulfasalazine. Recent evidence has demonstrated that targeted biologic response modifiers, such as TNF-alpha antagonists, are well tolerated and efficacious treatments for SpA. CONCLUSIONS: Significant advances have occurred in our understanding of the pathophysiology, diagnosis, and classification of the spondyloarthritides and effective treatments are available.
19010373 IL-6R distribution in normal human and cynomolgus monkey tissues. 2009 Feb Interleukin-6 (IL-6) is a pleiotropic cytokine and a contributing factor in many diseases such as rheumatoid arthritis, Castleman's disease, Crohn's disease, and multiple myeloma. Since the blockade of the signaling pathway of the IL-6/interleukin-6 receptor (IL-6R)/gp130 complex is considered to have therapeutic value in such diseases, we developed an IL-6R humanized antibody (tocilizumab). In the current report, distribution of IL-6R in both normal human and cynomolgus monkey tissues was assessed as fundamental data to support preclinical and clinical studies of tocilizumab. Human and cynomolgus monkey tissue panels were stained with commercially available anti-human IL-6R and a species- and isotype-matched negative antibody, as well as assay control slides. The detection system applied used an Envision immunoperoxidase staining procedure with DAB reaction. Positive reactions were observed in the tissue elements of lymphatic, hematopoietic, digestive, reproductive, exocrine, endocrine, neural, muscular, epidermal, respiratory, and urinary systems of the human and cynomolgus monkey tissue panels. The current report is inclusive of a wide variety of tissues and shows the distribution of IL-6R to be similar for both human and monkey tissues. We consider this information fundamental for the support and interpretation of preclinical and clinical studies of anti-IL-6R antibody therapy.
18973788 The role and regulation of 11beta-hydroxysteroid dehydrogenase type 1 in the inflammatory 2009 Mar 25 Cortisone, a glucocorticoid hormone, was first used to treat rheumatoid arthritis in humans in the late 1940s, for which Hench, Reichstein and Kendall were awarded a Nobel Prize in 1950 and which led to the discovery of the anti-inflammatory effects of glucocorticoids. To be effective, the intrinsically inert cortisone must be converted to the active glucocorticoid, cortisol, by the intracellular action of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Whilst orally administered cortisone is rapidly converted to the active hormone, cortisol, by first pass metabolism in the liver, recent work has highlighted an anti-inflammatory role for 11beta-HSD1 within specific tissues, including in leukocytes. Here, we review recent evidence pertaining to the anti-inflammatory role of 11beta-HSD1 and describe how inhibition of 11beta-HSD1, as widely proposed for treatment of metabolic disease, may impact upon inflammation. Finally, the mechanisms that regulate 11beta-HSD1 transcription will be discussed.
18812781 Combined use of superficial keratectomy and subconjunctival bevacizumab injection for corn 2008 Oct PURPOSE: To report the effect of superficial keratectomy combined with subconjunctival bevacizumab injection in 2 cases of corneal neovascularization (NV). METHODS: An interventional case series was undertaken on 2 patients with corneal NV: 1 due to sclerokeratitis secondary to rheumatoid arthritis and the other due to Terrien marginal degeneration. Both patients underwent superficial keratectomy combined with subconjunctival bevacizumab injection (2.5 mg/0.1 mL). RESULTS: Corneal NV regressed with the surgical removal and showed no signs of recurrence after 3 months of follow-up. Both patients reported dramatic subjective improvement in their vision within 1-2 weeks. Best corrected visual acuity improved in 1 patient. CONCLUSION: The combination of superficial keratectomy with subconjunctival injection of bevacizumab may offer a new strategy for the treatment of superficial corneal NV.
18808429 Telemedicine in wound care. 2008 Dec Telemedical wound care is one of the applications of teledermatology. We present our experience using telemedicine in the successful assessment and treatment of three patients with hard-to-heal ulcers. Three patients were seen at the PEMEX General Hospital in Veracruz, Mexico. The first patient was a 53-year-old man with hypertension, morbid obesity, chronic venous insufficiency, recurrent erysipelas, leg ulcers and lymphoedema. There was one ulcer on his left lower leg (20 x 10 cm) and one on his right leg (9 x 7 cm). The second patient was a 73-year-old woman with class III obesity and ulcers in her right leg, secondary to surgical debridement of bullous erysipelas. The third patient was a 51-year-old female with rheumatoid arthritis with one ulcer on each leg and chronic lymphostasis. Photographs with a digital camera were taken and sent weekly via email to a wound care specialist in Mexico City. The photographs allowed the expert to diagnose and evaluate the chronic wounds periodically. In the present cases, telemedicine allowed us to have a rapid evaluation, diagnosis and treatment. The images were of enough quality to be useful and small enough to be sent via regular email to the remote physician who immediately gave his feedback. The expert was confident to give therapeutic recommendations in this way, and we considered this method to be very cost-effective, saving the patient and the health care system, especially in transportation.
18755367 Tumor necrosis factor antagonists in the therapy of psoriasis. 2008 Sep The identification of new pathophysiological mechanisms in chronic inflammatory diseases and the development of techniques that allow production of antibodies and fusion proteins that antagonize target molecules with high specificity has not only revolutionized the treatment of rheumatoid arthritis and chronic inflammatory bowel disease, but it also has revolutionized the treatment of psoriasis in recent years. Two different classes of so-called biological therapies (biologics) have become available to treat psoriasis: tumor necrosis factor (TNF) antagonists and T-cell modulators. TNF antagonists that have been studied with psoriasis include the antibodies infliximab and adalimumab and the fusion protein etanercept. These treatments differ in their capacity to reduce the skin symptoms of psoriasis and other important characteristics of the drug profile. This article summarizes the important aspects of efficacy, safety, and practicability of TNF antagonists in the treatment of psoriasis. This article may be helpful for the daily routine when selecting the right therapy for a patient and managing the TNF antagonist during maintenance therapy.
18727021 Topical delivery of methotrexate via skin pretreated with physical enhancement techniques: 2008 Sep BACKGROUND AND OBJECTIVE: The high hydrophilicity and molecular weight of methotrexate (MTX) make it difficult to deliver via the skin route for treating psoriasis or rheumatoid arthritis. The objective of this study was to enhance and optimize the skin permeation of MTX using two physical techniques: an erbium:yttrium-aluminum-garnet (Er:YAG) laser and electroporation. METHODS: In vitro skin permeation was performed using horizontal side-by-side diffusion cells. The animal model utilized nude mice. The skin where epidermal hyperproliferation was reproduced by repeated barrier abrogation was also used as a permeation barrier for MTX delivery. RESULTS: Application of the laser and electroporation significantly enhanced the permeation of MTX. The enhancing effect was more pronounced after applying the laser. Er:YAG laser pretreatment on the skin produced a 3- to 80-fold enhancement dependent upon the magnitude of the laser fluence. Using electroporation, treatment with 10 pulses resulted in a twofold increase in MTX flux. A combination of laser pretreatment and subsequent electroporation for 10 minutes resulted in a higher drug permeation than either technique alone. However, this synergistic effect was only observed when the lower laser fluence (1.4 J/cm(2)) was applied. Hyperproliferative skin generally showed a greater variability of MTX flux and lower permeation. CONCLUSION: The results shown in the present study encourage further investigation of laser- and electroporation-assisted topical drug delivery.
18618354 G protein-coupled receptor kinase 2 (GRK2) in migration and inflammation. 2008 Jul G protein-coupled receptor kinase 2 (GRK2) is a key modulator of G protein-coupled receptors and other plasma membrane receptors stimulated by chemotactic messengers. On top of that, GRK2 has been reported to interact with a variety of signal transduction proteins related to cell migration such as MEK, Akt, PI3Kgamma or GIT. Interestingly, the levels of expression and activity of this kinase are altered in a number of inflammatory disorders (as rheumatoid arthritis or multiple sclerosis), thus suggesting that it may play an important role in the onset or development of these pathologies. This review summarizes the mechanisms involved in the control of GRK2 expression and function and highlights novel functional interactions of this protein that might help to explain how altered GRK2 levels affects cell migration in different cell types and pathological settings.
18590834 Osteopontin is dispensable for protection against high load systemic fungal infection. 2008 Oct Osteopontin (OPN) is a multi-functional cytokine which is involved in the pathogenesis of autoimmune disease. We previously reported that thrombin-cleaved form of OPN plays a pathogenic role in murine model of rheumatoid arthritis (RA) by using neutralizing antibody (M5) reacting against the cryptic epitope within OPN, exposed by thrombin cleavage of OPN. It has been shown that OPN-deficient mice are susceptible to various infections, demonstrating the protective role of OPN against various infectious diseases. However, it remains to be clarified whether and how OPN is involved in protection against systemic fungal infection. In a murine model of systemic fungal infection, OPN-deficient mice showed the increase in the susceptibility to low load, but not to high load fungal infection, indicating the protective of OPN against mild or severe forms of infections. However, mice treatment with M5 antibody did not alter the susceptibility to both high and low load fungal infection. These experiments suggest that in sharp contrast to the complete abrogation of OPN expression in OPN-deficient mice, the neutralization of OPN by antibody against thrombin-cleaved form of OPN does not interfere with the host defense against high and low load fungal infection. These findings suggest that the neutralizing antibody which is specific for the epitope of thrombin-cleaved OPN may become an attractive therapeutic means for the treatment of RA without interfering host defense system.