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ID PMID Title PublicationDate abstract
30235571 Academic Clinical Trials and Drug Regulations in Japan: Impacts of Introducing the Investi 2014 Jul In Japan, academic clinical trials do not generally need to be conducted under good clinical practice and cannot therefore be used for regulatory submission for marketing authorization of new medical products. We reviewed 2 differential regulatory systems governing clinical trials in Japan and the development histories of 2 case products whose clinical trials at the early development stage were conducted by academic researchers and transferred to the private sector for further development toward commercialization in Japan. We further estimated that the introduction of the investigational new drug system may have accelerated the development of tocilizumab, an antibody drug for rheumatoid arthritis, at best by 2 years by utilizing the results of early exploratory clinical trials conducted by academic investigators. Similarly, an enlarged indication for JACE(®), a cultured epithelium autograft for severe burns, would have been expected at launch by utilizing the results of academic trials investigating various indications. These possible impacts and estimations would warrant introducing the investigational new drug system into Japan drug regulatory system.
24709903 Development of a Novel BAFF Responsive Cell Line Suitable for Detecting Bioactive BAFF and 2014 Feb 10 BAFF has a critical role in B-cell survival, maturation and function, which makes its pathway a prime therapeutic target for various autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis and Sjögren's syndrome. A cell-based assay that measures the functional activity of BAFF is required for many high throughput purposes, such as lead target screening and BAFF quantification. We report here the development of a sensitive BAFF responsive cell line via stable transfection of the BAFFR-TNFR1 hybrid receptor into monkey kidney epithelial COS-1 cells. The cellular response to BAFF can be detected by measuring the secretion of IL-8. This BAFF bioassay is not only reproducible and sensitive, but also responsive to a wide concentration range of BAFF stimulation in sera from various species. This cell line is useful in the development of sensitive bioassays to measure the levels of bioactive BAFF, inhibition of BAFF and neutralizing antibodies against any BAFF pathway-mediated therapeutic proteins.
24331794 Vasculitic neuropathies. 2014 Jan The vasculitic neuropathies are a diverse group of disorders characterised by the acute-to-subacute onset of painful sensory and motor deficits that result from inflammatory destruction of nerve blood vessels and subsequent ischaemic injury. They are common in patients with primary systemic vasculitis and are seen in vasculitis secondary to disorders such as rheumatoid arthritis, viral infections, and diabetic inflammatory neuropathies. It is imperative that neurologists recognise these disorders to initiate treatment promptly and thereby prevent morbidity and mortality. To simplify the approach to patients with vasculitis of the peripheral nerves, a straightforward, dichotomous classification scheme can be used in which the vasculitic neuropathies are divided into two groups-nerve large arteriole vasculitis and nerve microvasculitis-on the basis of the size of the involved vessels. The size of the affected blood vessels correlates with the clinical course and prognosis in patients with vasculitic neuropathy.
24312814 Design and characterization of microemulsion systems for naproxen. 2013 PURPOSE: This research was aimed to formulate and characterize a microemolsion systems as a topical delivery system of naproxen for relief of symptoms of rheumatoid arthritis, osteoarthritis and treatment of dysmenorrheal. METHODS: ME formulations prepared by mixing of appropriate amount of surfactant including Tween 80 and Span 80, co-surfactant such as propylene glycol (PG) and oil phase including Labrafac PG - transcutol P (10:1 ratio). The prepared microemolsions were evaluated regarding their particle size, zeta potential, conductivity, stability, viscosity, differential scanning calorimetry (DSC), scanning electron microscopy (SEM), refractory index (RI) and pH. RESULTS: The mean droplets size of microemulsion formulation were in the range of 7.03 to 79.8 nm, and its refractory index (RI) and pH were 1.45 and 6.75, respectively. Viscosity range was 253.73- 802.63cps. Drug release profile showed that 26.15% of the drug released in the first 24 hours of experiment. Also, Hexagonal and bicontinuous structures were seen in the SEM photograph of the microemulsions. CONCLUSION: characterization, physicochemical properties and in vitro release were dependent upon the contents of S/C ratio, water and, oil phase percentage in formulations. Also, ME-6 may be preferable for topical naproxen formulation.
23828150 Antibiotic resistance: a "dark side" of biofilm‑associated chronic infections. 2013 Bacteria may exist in nature in a planktonic form or in biofilms that allow bacteria to survive in an unfriendly microenvironment. Biofilm is a structured community of bacteria hidden in a self-produced polymeric matrix of polysaccharides, proteins, and extracellular DNA. Biofilm-growing bacteria cause chronic infections, which are characterized by persisting inflammation and tissue damage (chronic rhinosinusitis, chronic wounds, periodontal diseases). Importantly, some bacteria of human microbiome, when growing in a biofilm (e.g., Porphyromonas gingivalis in dental plaque), can become destructive and can contribute to an association between local infections (periodontitis) and systemic diseases such as atherosclerosis or rheumatoid arthritis. The biggest clinical challenge with biofilm-associated infections is their high resistance to antibiotic therapy. Therefore, biofilm formation should be prevented either by antibiotic prophylaxis or early aggressive pharmacological therapy. In this review, we also discuss novel antibiofilm therapeutic strategies based on compounds that can destroy the biofilm matrix and increase susceptibility of biofilm-forming bacteria to antibiotics and host defense system.
23730882 Spondyloarthritis and smoking: towards a new insight into the disease. 2013 Jun In spondyloarthritis, smoking was found in several studies from the literature to be associated with earlier onset, more severe disease in activity, function, quality of life and imaging (inflammatory and structural lesions), sometimes in a dose-dependent manner. Smoking is also associated with elevated inflammatory biologic parameters (e.g., C-reactive protein). Periodontitis, associated with smoking, is more frequent in patients with ankylosing spondylitis as compared with controls. This periodontal disease may favor citrullination, as in rheumatoid arthritis. Citrullinated vimentin has been demonstrated to be associated with radiographic damage. In this line, smoking was found to be associated with matrix metalloproteinase levels, which is also a predictive factor for spinal radiographic progression. Finally, smoking has a negative influence on bronchopulmonary and cardiovascular outcomes, already impaired by the disease itself. Smoking represents a target for therapeutic impact and disease modification in spondyloarthritis.
23664525 Immune thrombocytopenia and B-cell-activating factor/a proliferation-inducing ligand. 2013 Jan Primary immune thrombocytopenia (ITP) is an organ-specific autoimmune disorder characterized by autoantibody-mediated enhanced platelet destruction and dysmegakaryocytopoiesis. B cells have been demonstrated to play critical roles in the pathophysiology of ITP. B-cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are crucial cytokines supporting survival and differentiation of B cells, and dysregulation of BAFF/APRIL is involved in the pathogenesis of B-cell related autoimmune diseases including ITP. Currently ongoing clinical trials using BAFF and/or APRIL-blocking agents have yielded positive results in human systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), further confirming the pathological role of BAFF/APRIL in autoimmunity. This review will describe the function of BAFF/APRIL and address the feasibility of BAFF/APRIL inhibition in the management of ITP.
23665311 Bilateral rupture of the extensor pollicis longus tendon. A case report. 2013 Jun Bilateral rupture of the extensor pollicis longus (EPL) is a rare entity and the few cases that have been reported were associated with an underlying systemic condition such as rheumatoid arthritis or following an injury. We present the case of a patient who was referred to us with a spontaneous rupture of the EPL tendon of the right wrist and that of the left side observed 2 months after tenosynovectomy. The patient had not any pathologic condition or evidence of trauma in both wrists. In the left side, he was operated on and a tenolysis and subcutaneous tendon transposition was performed. Despite this preventive surgery, the patient suffered from a tendon rupture. The possible causes of surgery failure are discussed.
23403170 Compound f: the history of hydrocortisone and hand surgery. 2013 Apr Hydrocortisone (cortisol) is used daily in the practice of medicine and hand surgery. It has an effective use in a number of orthopedic conditions, including tendinitis, tenovaginitis, bursitis, carpal tunnel syndrome, and joint inflammation. But are surgeons aware of how this important pharmaceutical agent was discovered and prepared for clinical trial and who was responsible for its first clinical application? How did medical doctors determine that, like penicillin, cortisone and its derivative hydrocortisone would have such a life-changing effect on certain medical conditions? The purpose of this review is to relate the story of the development of cortisone (Compound E) and hydrocortisone (Compound F) and how both influenced the practice of hand surgeons in the treatment of rheumatoid arthritis and related inflammatory conditions. This history of cortisone and hydrocortisone also relates to the importance of partnership between physician and research scientist and of the principle at Mayo Clinic that the only concern--or the first concern--is the concern for the patient.
23175390 The protein arginine deiminases: Structure, function, inhibition, and disease. 2013 Feb The post-translational modification of histones has significant effects on overall chromatin function. One such modification is citrullination, which is catalyzed by the protein arginine deiminases (PADs), a unique family of enzymes that catalyzes the hydrolysis of peptidyl-arginine to form peptidyl-citrulline on histones, fibrinogen, and other biologically relevant proteins. Overexpression and/or increased PAD activity is observed in several diseases, including rheumatoid arthritis, Alzheimer's disease, multiple sclerosis, lupus, Parkinson's disease, and cancer. This review discusses the important structural and mechanistic characteristics of the PADs, as well as recent investigations into the role of the PADs in increasing disease severity in RA and colitis and the importance of PAD activity in mediating neutrophil extracellular trap formation through chromatin decondensation. Lastly, efforts to develop PAD inhibitors with excellent potency, selectivity and in vivo efficacy are discussed, highlighting the most promising inhibitors.
24911335 Anti-inflammatory and antioxidant activities of Costus afer Ker Gawl. hexane leaf fraction 2014 Aug 8 ETHNOPHARMACOLOGICAL RELEVANCE: Costus afer Ker Gawl is an indigenous tropical African medicinal plant used as therapy in the treatment of inflammatory ailments such as rheumatoid arthritis. This study was designed to evaluate the anti-inflammatory and antioxidant activities of the hexane fraction of C. afer leaves (CAHLF). MATERIALS AND METHODS: The anti-inflammatory effect of varying doses of CAHLF on carrageenan, arachidonic acid, and formaldehyde induced arthritis in male albino rats׳ models were investigated in order to study the acute inflammatory phase. Complete Freund׳s Adjuvant (CFA)-induced arthritis model was used to study the chronic inflammatory phase. Two known anti-inflammatory drugs, Diclofenac sodium (non-steroidal anti-inflammatory drug [NSAID]) and prednisolone (glucocorticoid [steroidal drug]) were used as standards for comparison. Various biochemical indices viz. superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), reduced glutathione (GSH) and malondialdehyde (MDA), aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase (ALP), total bilirubin (TB), total protein (TP), globulin and albumin levels were assayed using spectrophotometric methods. RESULTS: Control animals in which arthritis have been induced using carrageenan, arachidonic acid, formaldehyde or CFA showed significant increases (P<0.05) in paw edema when compared with normal animals. Treatment of the arthritis induced rats with CAHLF significantly (P<0.05) suppressed the edema. in vivo antioxidant study showed that CAHLF treated animals had a significantly (P<0.05) elevated GSH level, SOD, CAT and GST activities while MDA levels were significantly (P<0.05) reduced in the plasma, liver, kidney and brain. CAHLF treated rats had a significantly (P<0.05) reduced plasma AST, ALT and ALP. Plasma TP, globulin, TB levels were reduced while albumin levels were elevated in CAHLF treated animals. CONCLUSIONS: CAHLF possesses substantial anti-inflammatory and antioxidant activities against inflammatory diseases especially arthritis. It could be considered as a choice candidate in pharmaceutical anti-inflammatory drug development.
24796746 [Mechanism of cardiac function changes in rat models of Sjogren's syndrome based on Keap1- 2014 May OBJECTIVE: To investigate the mechanism underlying the changes in the cardiac function in rat models of Sjogren's syndrome (SS) based on Kelch-like ECH-associated protein 1 (Keap1)-Nrf2/ARE signaling pathways. METHODS: Thirty male Wistar rats were randomly divided into two groups, normal control (NC) group and SS model group, with 15 in each. The rats in the model group were injected with the complete Freund's adjuvant plus homologous antigen of submandibular gland (0.2 mL mixture) into bilateral posterior paw metatarsus. The body mass, water intake, submandibular gland index, spleen index, and histological changes of the glands were observed 30 days after inflammation was induced. Cardiac function was assessed using invasive hemodynamic monitoring. Meanwhile, reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) and total antioxidant capacity (TAC), IL-18, IL-35 were detected using ELISA; ROS and reactive nitrogen species (RNS), glutathione (GSH), thioredoxin (TrX) protein were determined using immunohistochemical staining. The expressions of Keap 1, nuclear factor erythroid 2-related factor (Nrf2), macrophage activating factor (Maf) antioxidant responsive element (ARE) mRNAs were detected using real-time fluorescent quantitative PCR (qRT-PCR); the levels of heme oxygenase-1 (HO-1), γ-glutamic acid and a half long glycine synthetase (γ-GCS) proteins in cardiac tissue were examined using Western blotting. RESULTS: Compared with the NC group, the model group presented reduced body mass, submandibular gland index and spleen index (P<0.05), increased water intake (P<0.01), heart rate (HR), heart index (HI), left ventricular systolic pressure (LVSP) and left ventricular diastolic pressure (LVEDP) (P<0.05), and decreased left ventricular ±dp/dtmax (P<0.05). Compared with the NC group, the model group had increased IL-18, MDA, RNS, TAC, ROS levels, and Keap1, Maf, Nfr2 mRNAs, HO-1, γ-GCS protein expressions in the heart tissue, while TrX, GSH, IL-5 and SOD levels decreased significantly (P<0.01). CONCLUSION: The immune imbalance in SS rats may be related with the up-regulated levels of Keap1, Maf, Nfr2 mRNAs, HO-1, γ-GCS.
24551030 Matriptase deletion initiates a Sjögren's syndrome-like disease in mice. 2014 OBJECTIVE: The objective of this study was to determine the effect of epithelial barrier disruption, caused by deficiency of the membrane-anchored serine protease, matriptase, on salivary gland function and the induction of autoimmunity in an animal model. METHODS: Embryonic and acute ablation of matriptase expression in the salivary glands of mice was induced, leading to decreased epithelial barrier function. Mice were characterized for secretory epithelial function and the induction of autoimmunity including salivary and lacrimal gland dysfunction, lymphocytic infiltration, serum anti-Ro/SSA, anti-La/SSB and antinuclear antibodies. Salivary glands immune activation/regulation, barrier function as well as tight junction proteins expression also were determined. Expression of matriptase in minor salivary gland biopsies was compared among pSS patients and healthy volunteers. RESULTS: Embryonic ablation of matriptase expression in mice resulted in the loss of secretory epithelial cell function and the induction of autoimmunity similar to that observed in primary Sjögren's syndrome. Phenotypic changes included exocrine gland dysfunction, lymphocytic infiltrates, production of Sjögren's syndrome-specific autoantibodies, and overall activation of the immune system. Acute ablation of matriptase expression resulted in significant salivary gland dysfunction in the absence of overt immune activation. Analysis of the salivary glands indicates a loss of electrical potential across the epithelial layer as well as altered distribution of a tight junction protein. Moreover, a significant decrease in matriptase gene expression was detected in the minor salivary glands of pSS patients compared with healthy volunteers. CONCLUSIONS: Our findings demonstrate that local impairment of epithelial barrier function can lead to loss of exocrine gland function [corrected] in the absence of inflammation while systemic deletion can induce a primary Sjögren's syndrome like phenotype with autoimmunity and loss of gland function.
23925155 An immunohistochemistry-based study on aquaporin (AQP)-1, 3, 4, 5 and 8 in the parotid gla 2013 Cevimeline is a muscarinic agonist that promotes saliva secretion and is used to treat Sjögren's syndrome (SS), an autoimmune disorder in which the exocrine glands that produce saliva are destroyed. Cevimeline is thought to affect the composition of saliva in part by regulating the localization of aquaporins (AQPs). In this study, we investigated the effects of chronic Cevimeline administration in the salivary glands of SS mice on the immunohistochemical localization of aquaporin (AQP)-1, 3, 4, 5 and 8. We used Cevimeline-untreated SS mice, treated SS mice, discontinued SS mice and untreated normal mice. AQP-5 was found in the apical and lateral membranes of acinar cells in the parotid and submandibular glands of cevimeline-treated SS mice and untreated normal mice. Saliva secretion and AQP-5 localization were sustained in SS mice who were chronically administered Cevimeline and at four weeks after discontinuation. Unlike AQP-5, the localization of AQP-1, 3, 4 and 8 were not affected by Cevimeline administration. Our findings demonstrated that administration of Cevimeline maintains the proper localization of AQP-5 in the acinar cells of the salivary gland, which may promote salivation in chronically treated SS mice. Clinically, this suggests that chronic Cevimeline administration may be useful therapeutically for SS patients suffering from a decrease in saliva secretion by improving the disordered AQP-5 localization.
23679844 The important role of T cells and receptor expression in Sjögren's syndrome. 2013 Aug Sjögren's syndrome (SjS), an autoimmune disease characterized by exocrine gland dysfunction leading to dry mouth and dry eye diseases, is typified by progressive leucocyte infiltrations of the salivary and lacrimal glands. Histologically, these leucocyte infiltrations generally establish periductal aggregates, referred to as lymphocytic foci (LF), which occasionally appear as germinal centre (GC)-like structures. The formation and organization of these LF suggest an important and dynamic role for helper T cells (TH), specifically TH1, TH2 and the recently discovered TH17, in development and onset of clinical SjS, considered a B cell-mediated hypersensitivity type 2 disease. Despite an ever-increasing focus on identifying the underlying aetiology of SjS, defining factors that initiate this autoimmune disease remain a mystery. Thus, determining interactions between infiltrating TH cells and exocrine gland tissue (auto-)antigens represents a fertile research endeavour. This review discusses pathological functions of TH cells in SjS, the current status of TH cell receptor gene rearrangements associated with human and mouse models of SjS and potential future prospects for identifying receptor-autoantigen interactions.
23225089 Safety and efficacy of 0.1% clobetasone butyrate eyedrops in the treatment of dry eye in S 2013 May PURPOSE: To study the effects of a low administration rate and low concentration (0.1%) of clobetasone butyrate eyedrops in patients with Sjögren syndrome (SS).
 METHODS: This prospective, double-masked, randomized, placebo-controlled study included 40 subjects divided into 2 treatment groups: group 1 (2% polyvinylpyrrolidone eyedrops and placebo) and group 2 (2% polyvinylpyrrolidone and 0.1% clobetasone butyrate, 1 drop BID). The treatment lasted for 30 days, with visits at enrollment, baseline, day 15, day 30, and after 15 days of treatment discontinuation. At each visit, symptoms questionnaire, tear film break-up time, corneal fluorescein stain, lissamine green stain, conjunctival impression cytology for human leukocyte antigen-DR (HLA-DR) expression, intraocular pressure (IOP) measurement, and fundus examination were performed. 
 RESULTS: No changes in IOP or fundus examination were observed in either group at each time point. Group 1 patients showed at day 30 a statistically significant amelioration of symptoms and reduction of HLA-DR expression. No changes in other parameters were detected. Group 2 patients showed at day 15 a statistically significant improvement of corneal and conjunctival stain versus baseline values and group 1 at the same time; after 30 days the symptoms score was statistically significantly better than baseline values and group 1 at the same time. The HLA-DR expression and the epithelial cells area were statistically significantly reduced versus baseline and group 1 at the same time. 
 CONCLUSIONS: Anti-inflammatory therapy is critical for the treatment of SS dry eye. Clobetasone butyrate, at low dosage, proved to be safe and effective in treating this condition.
23632764 Evolution of transoral surgery: three decades of change in patients, pathologies, and indi 2013 Aug BACKGROUND: Transoral surgery may be used to approach pathologies at the craniocervical junction. However, the need for this approach has decreased over the past few decades. OBJECTIVE: To assess the outcome and complications of transoral surgery and extended transoral approaches at a single UK center between 1980 and 2011. METHODS: A retrospective review was performed of 495 ventral midline operations (between 1980 and 2004) and prospective review of 38 operations (2004-2011) in a total of 479 patients. Trends in surgery and factors associated with good or bad outcome were assessed over this 30-year period. RESULTS: Of 533 operations, the most frequently performed surgeries were simple transoral surgery (321 operations), transoral surgery with splitting of the palate (107 operations), open-door maxillotomy (58 operations), and mandibulotomy (11 operations). Since the 1990s, there has been a steady decrease in the number of operations performed, mainly due to the decrease in the number of patients with rheumatoid arthritis presenting for surgery. The incidence of craniocervical junction tumors remained constant. The number of complications was significantly associated with the preoperative neurological status, and more complications were seen in myelopathic rheumatoid patients as well as a greater trend in congenital basilar invagination. The rates of pharyngeal infection (0.6%) and cerebrospinal fluid leak (0.3%) for standard transoral surgery were extremely low. CONCLUSION: The number of transoral and associated operations has decreased over time. Transoral surgery is now mainly indicated for ventral midline tumors such as chordomas. Transnasal endoscopic techniques show promise, but a major advantage of standard transoral surgery is the low cerebrospinal fluid leak and infection rates.
25839959 Parvovirus B19 infection as a cause of acute myositis in an adult. 2015 Mar Parvovirus B19 infection is often asymptomatic, but clinical expressions may include transient aplastic crisis, erythema infectiosum, non-immune hydrops fetalis, and chronic red cell aplasia. This virus has also been associated with rheumatoid arthritis and other autoimmune connective tissue diseases; however, we could not identify any acute adult myositis case developed after a Parvovirus B19 infection in the literature. For this reason, we would like to present a rare case of acute myositis developed after Parvovirus B19 infection. In patients presenting with symptoms of fever, rash on the legs and myositis, viral infections such as Parvovirus B19 should be kept in mind.
25365083 Optimising ultrasonography in rheumatology. 2014 Sep Ultrasonography is an imaging modality that has been utilised in clinical medicine since the 1950s. However, application to joints and rheumatic disease was delayed until appropriate advances in technology made it feasible. Since the 1990s, rheumatologists have embraced ultrasonography as a useful clinical tool and it has increasingly been applied in routine practice. Initial criticism correctly focused on a lack of validity data, recognition that this modality is highly user-dependent and that reliability was not established. In response, the rheumatological community identified relevant pathologies to study, starting with synovitis in rheumatoid arthritis, and set about defining the ultrasound abnormalities, followed by demonstrating the validity, reproducibility and responsiveness of these measures. Much work is now ongoing in the areas of enthesitis, gout and osteoarthritis. Additionally, the evidence base for ultrasonography in clinical practice is being investigated, in order to understand its appropriate place. Given the sensitivity of ultrasonography over clinical examination for detection of inflammation, this work will focus on its role in optimising diagnosis, directing therapy through accurate assessment of disease activity and understanding the optimal selection of joints for feasible disease monitoring. This review summarises the work undertaken to date, ongoing work and future challenges of optimising the role of ultrasonography in rheumatology.
24829195 Anti-ruthenium antibodies mimic macro-TSH in electrochemiluminescent immunoassay. 2014 Nov BACKGROUND: Macro-hormones are circulating conjugates of hormones with immunoglobulins, which often artefactually elevate biochemical test results. Particularly when causing only moderate elevation no suspicion will be raised. By far the most frequently encountered macro-hormone is macro-prolactin. Here we report a female patient with rheumatoid arthritis who had persistently and grossly elevated thyroid stimulating hormone (TSH) but normal free thyroxine in electrochemiluminescent assays. Although clinically euthyroid, she was put on thyroxine therapy which caused hyperthyroid symptoms. METHODS: An analytic interference by macro-TSH was assumed by dilution experiments, polyethylene-glycol-precipitation, the addition of a heterophilic antibody blocking reagent and size exclusion chromatography. RESULTS: Further workup, however, revealed the presence of anti-ruthenium antibodies. CONCLUSIONS: To our knowledge this is the first report of anti-ruthenium antibodies selectively interfering with a TSH assay and causing erratic gross elevation of TSH mimicking macro-TSH.