Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
24887053 Slipped capital femoral epiphysis in identical twins: does human leucocyte antigen matter? 2014 Sep Slipped capital femoral epiphysis (SCFE) is a well-known disorder of the hip in adolescents that is characterized by displacement of the capital femoral epiphysis from the metaphysis through the physis. Multiple theories have been proposed for the aetiology of idiopathic SCFE, and it is likely a result of both biomechanical and biochemical factors. The association between human leucocyte antigen (HLA) and certain rheumatic diseases is well established. One of the strongest associations is between the HLA class I antigen B27 and ankylosing spondylitis. Several DRB 1 alleles are associated with susceptibility to and severity of rheumatoid arthritis. The quest to find similar markers have fuelled the suggestion that SCFE may be linked to the presence of a specific HLA antigen. We present a case report of an identical twin presenting with SCFE. An 11-year-old girl presented with pain in her hip for last few days and difficulty in mobilizing. Radiographs showed SCFE that was fixed in situ with one screw. Eighteen months later her twin sister presented with pain in hip and limp of 3-week duration with no preceding history of trauma. Radiographs showed SCFE that was fixed in situ with one screw. Both sisters have made full recovery with no pain or residual limp. HLA typing of the twins showed variations between diseases and HLA phenotype in different population groups with SCFE. This is the fifth case of identical twins presenting with SCFE with HLA class I analysis and only the second case report with both HLA class I and class II analysis. Our case report further emphasizes findings from previous studies that there is no relationship between SCFE and a specific HLA class I or class II antigen. LEVEL OF EVIDENCE: Level V.
24844303 Therapeutic potential of STAT4 in autoimmunity. 2014 Aug INTRODUCTION: STAT4, which acts as the major signaling transducing STATs in response to IL-12, is a central mediator in generating inflammation during protective immune responses and immune-mediated diseases. AREAS COVERED: This review summarizes that STAT4 is essential for the differentiation and function of a wide variety of immune cells, including natural killer cells, mast cells, dendritic cells and T helper cells. In addition, STAT4-mediated signaling promoted the production of autoimmune-associated components, which are implicated in the pathogenesis of autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis and psoriasis. EXPERT OPINION: Due to its crucial roles in inflammation and autoimmunity, STAT4 may have promise as an effective therapeutic target for autoimmune diseases. Understanding the molecular mechanisms driving STAT4, together with knowledge on the ability of current immunosuppressive treatment to target this process, may open an avenue to novel therapeutic options.
24673442 Tenosynovitis with rice body formation presenting as a cutaneous abscess. 2014 Jul A 62-year-old woman with a past medical history of rheumatoid arthritis was referred to the Department of Dermatology because of an enlarging cutaneous lesion on the right thumb which resembled a soft tissue infection. She had received antibiotics without significant improvement. Clinical examination revealed an erythematous nodule involving almost the whole surface of the distal phalanx with spontaneous drainage of countless of small yellowish ovoid granules. Histopathologic study of these structures showed an inner core of amorphous acidophilic material with some interspersed chronic inflammatory cells and a surrounding thin fibrin layer. Special stains and cultures were negative for parasites, bacterium and mycobacterium. Magnetic resonance imaging (MRI) revealed distension of the first and fifth finger flexor sheaths and common finger flexor sheath. These areas were filled by fluid and multiple small nodular lesions. A diagnosis of non-infectious rice body tenosynovitis was rendered and surgical removal was performed. Total recovery was observed with no evidence of recurrence after 6 months of follow-up. To our knowledge, this is the first report of rice body tenosynovitis presenting as a pseudoinflammatory cutaneous lesion with evolution to a cutaneous fistula with drainage of rice grain-like structures. The description of this impressive and peculiar clinical and histopathologic picture is important to further recognize similar cases.
24633464 Absolute bioavailability and metabolism of aceclofenac in rats. 2015 Jan Aceclofenac is one of the most popular analgesic and anti-inflammatory drugs used for the relief of pain, rheumatoid arthritis, and osteoarthritis. To date, no intravenous preparation of aceclofenac has been developed because of its poor water solubility. In this study, to investigate its absolute bioavailability and metabolism in rats, aceclofenac was dissolved in a sterile aqueous solution containing urea (20 %) and trisodium citrate (10 %), and administered via oral (20 mg/kg) and intravenous (10 mg/kg) routes. Blood samples were taken serially, and aceclofenac and its three major metabolites (4'-hydroxydiclofenac, 4'-hydroxyaceclofenac, and diclofenac) were measured by HPLC-MS/MS. The absolute oral bioavailability of aceclofenac was approximately 15 %. Diclofenac and 4'-hydroxydiclofenac were the main metabolites in rats, in contrast to 4'-hydroxyaceclofenac in humans. The low bioavailability of aceclofenac is likely due to extensive metabolism, and bioavailability may be even lower if the drug were administered as a tablet, considering its low water solubility. This study provides complete time profiles of the plasma concentrations of aceclofenac and its metabolites in rats and highlights the difference in drug metabolism between rats and humans.
24583775 4-Amino-pyrrolopyridine-5-carboxamide: a novel scaffold for JAK1-selective inhibitors. 2014 Despite a high level of interest in selective Janus kinase 1 (JAK1) inhibitors and their potential for the treatment of inflammatory diseases such as rheumatoid arthritis (RA), only a few such inhibitors have been reported to date. In this study, a novel 4-amino-1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold was designed through structural modification of the potent JAK1-selective inhibitor, C2-methyl imidazopyrrolopyridine. Among the series studied, the 4-(2-aminoethyl)amino-pyrrolopyridine derivative, 2j, exhibited a significant 24.7-fold JAK1/JAK2 selectivity along with reasonable inhibitory activity against JAK1 (IC50=2.2 µM). The noticeable JAK1-selectivity of 2j was then tackled through a molecular docking study, which showed that the aminoethyl functionality of 2j is well positioned to discriminate the subtle but significant difference in the size of the ligand binding sites between JAK1 and JAK2.
24570644 Reconstruction of swan neck deformities after proximal interphalangeal joint arthroplasty. 2014 Mar BACKGROUND: The authors report the use of a single slip of the flexor digitorum superficialis (FDS) as a hemitenodesis through the A2 pulley in treating swan neck deformities after previous unconstrained proximal interphalangeal joint (PIP) arthroplasty. METHODS: A retrospective chart review was undertaken to identify non-constrained PIP joint arthroplasties that underwent a subsequent soft tissue hemitenodesis for swan neck deformities. The range of motion (ROM), implant design, preoperative diagnosis, and surgical approach were collected. The Michigan Hand Outcomes Questionnaire and patient satisfaction questionnaire were collected. RESULTS: There were 12 patients with 14 procedures reviewed. There were seven surface replacement arthroplasties (SRA) (cobalt chrome on polyethylene) and eight pyrocarbon prostheses. The primary diagnosis for the initial joint arthroplasty was osteoarthritis (8), post-traumatic (2), and rheumatoid arthritis (5). The primary dorsal approach was a longitudinal split in eleven cases, Chamay in two, and unknown in one case. Nine of the 14 revision procedures had a concomitant dorsal approach to the joint. The average final position intraoperatively was 24.2° of flexion (range 15°-40°). Final ROM was 39° with average follow-up of 30 months. The average postoperative radiographic position was 20.3° flexion with an average of 24.8° hyperextension preoperatively. There was one failure secondary to implant loosening requiring fusion. DISCUSSION: For patients with a swan neck deformity after PIP arthroplasty, a FDS hemitenodesis provides a treatment option with a low revision rate, retained motion, and maintenance of the original implant with no shortening of the digit.
24502314 Low-dose methotrexate - a therapeutical kick in TNF-alpha antagonist treatment for recalci 2014 Jan In contrast to the treatment of rheumatoid arthritis, there are few data in psoriasis vulgaris regarding the efficacy of combining tumor necrosis factor (TNF)-alpha inhibitors and methotrexate (MTX). Indeed, combination of MTX with different TNF-alpha inhibitors may enhance the therapeutic effects and reduce side effects because of less dosage of the single agent. The present authors present five cases in which low-dose MTX combined with TNF-alpha inhibitors led to impressive improvement in Psoriasis Area and Severity Index scores. Here, the present authors initiated very low-dose MTX treatment in addition to existing TNF-alpha inhibitor therapy to exhaust current therapy and prevent premature change of the biologic. These observations support the concept of combined treatment in recalcitrant cases of psoriasis, which need a systemically lifelong treatment when both first-line and second-line monotherapies fail to provide sufficient clinical response.
24474664 Peptides targeting chemokine receptor CXCR4: structural behavior and biological binding st 2014 Apr CXCR4 is a G-protein-coupled receptor involved in a number of physiological processes in the hematopoietic and immune systems. CXCL12/CXCR4 axis plays a central role in diseases, such as HIV, cancer, WHIM syndrome, rheumatoid arthritis, pulmonary fibrosis, and lupus and, hence, indicated as putative therapeutic target. Although multiple CXCR4 antagonists have been developed, there is only one marketed drug, plerixafor, indicated for stem cell mobilization in poor mobilizer patients. In this work, we have designed and synthesized two peptides, six and seven residues long, using as template the N-terminal region of CXCL12; analyzed their conformations by CD, NMR, and molecular dynamics simulations; simulated their complexes with CXCR4 by docking methods; and validated these data by in vitro studies. The results showed that the two peptides are rather flexible in aqueous solution lacking ordered secondary structure elements and present a promising affinity for CXCR4. This affinity is not revealed for CXCR7, indicating a specificity for CXCR4.
24471412 Importance of sphingosine kinase (SphK) as a target in developing cancer therapeutics and 2014 Jul 10 Sphingosine kinase (SphK) is an oncogenic lipid kinase that regulates the sphingolipid metabolic pathway that has been shown to play a role in numerous hyperproliferative/inflammatory diseases. The SphK isoforms (SphK1 and SphK2) catalyze the conversion of the proapoptotic substrate d-erythrosphingosine to the promitogenic/migratory product sphingosine 1-phosphate (S1P). Accumulation of S1P has been linked to the development/progression of cancer and various other diseases including, but not limited to, asthma, inflammatory bowel disease, rheumatoid arthritis, and diabetic nephropathy. SphK therefore represents a potential new target for developing novel therapeutics for cancer and other diseases. This finding has stimulated the development and evaluation of numerous SphK inhibitors over the past decade or so. In this review, we highlight the recent advancement in the field of SphK inhibitors including SphK1 and SphK2 specific inhibitors. Both sphingolipid based and nolipidic small molecule inhibitors and their importance in treatment of cancer and other diseases are discussed.
24353496 Mixed connective tissue disease presenting with progressive scleroderma symptoms in a 10-y 2013 Oct Mixed connective tissue disease (MCTD) is a systemic inflammatory disease affecting connective tissue with the underlying autoimmunological mechanism. The core of MCTD is an appearance of symptoms of several other inflammatory diseases of connective tissue - systemic lupus erythematosus, systemic scleroderma, poly- or dermatomyositis, rheumatoid arthritis at the same time, accompanied by a high level of anti-ribonucleoprotein antibodies (anti-U1RNP). The disease was described more than 40 years ago by Sharp et al. During recent years, many efforts to better understand clinical and serological features of MCTD have been made. Diagnosis of MCTD can be difficult. Obligatory international diagnostic criteria are required to be fulfilled. Several versions of such criteria have been proposed, but the most widely used one was described by Kasukawa. There is no consensus about treatment - a choice of drugs depends on symptoms. We present a case of a 10-year-old girl with sclerodactyly and trophic damages of fingers accompanied by symptoms of Raynaud's phenomenon. After an almost 2-year course of the disease, a diagnosis of MCTD has been established.
24313993 Galectin-3: its role in asthma and potential as an anti-inflammatory target. 2013 Dec 9 Galectins constitute an evolutionary conserved family that bind to β-galactosides. Increasing evidence shows that galectins are involved in many fundamental biological processes such as cellular communication, inflammation, differentiation and apoptosis. Changes in galectin-3 (Gal-3) expression are commonly seen in cancer and pre-cancerous conditions, and Gal-3 may be involved in the regulation of diverse cancer cell activities that contribute to tumourigenesis, cancer progression and metastasis. In addition, Gal-3 is a pro-inflammatory regulator in rheumatoid arthritis. Gal-3 has been shown to be involved in many aspects in allergic inflammation, such as eosinophil recruitment, airway remodeling, development of a Th2 phenotype as well as increased expression of inflammatory mediators. In an in vivo model it was shown that bronchoalveolar lavage (BAL) fluid from ovalbumin-challenged mice contained significantly higher levels of Gal-3 compared to control mice. The molecular mechanisms of Gal-3 in human asthma have not been fully elucidated. This review will focus on what is known about the Gal-3 and its role in the pathophysiological mechanisms of asthma to evaluate the potential of Gal-3 as a biomarker and therapeutic target of asthma.
24259122 Reproducible quantification of osteoclastic activity: characterization of a biomimetic cal 2014 Jul Osteoclasts are responsible for bone and joint destruction in rheumatoid arthritis, periodontitis, and osteoporosis. Animal tusk slice assays are standard for evaluating the effect of therapeutics on these cells. However, in addition to batch-to-batch variability inherent to animal tusks, their use is clearly not sustainable. Our objective was to develop and characterize a biomimetic calcium phosphate assay based on the use of phase pure hydroxyapatite coated as a thin film on the surface of culture plates, to facilitate the reproducible quantification of osteoclast resorptive activity. Osteoclasts were formed from RAW 264.7 mouse monocyte cell line using a pro-resorptive cytokine RANKL (50 ng/mL). No change in substrate appearance was noted after culture with media without cells, or undifferentiated monocytes. Only in the presence of osteoclasts localized areas of calcium phosphate dissolution were observed. The total area resorbed positively correlated with the osteoclast numbers (R(2) = 0.99). The resorbed area was significantly increased by the addition of RANKL, and decreased after application of known inhibitors of osteoclast resorptive activity, calcitonin (10 μM), or alendronate (100 μM). Thus, calcium phosphate coated substrates allow reliable monitoring of osteoclast resorptive activity and offer an alternative to animal tusk slice assays.
24204110 Are cataracts associated with osteoporosis? 2013 BACKGROUND: Calcium is considered an important factor in the development of both osteoporosis and cataract. This study evaluated the association between osteoporosis and cataracts. OBJECTIVE: To evaluate the prevalence of osteoporosis among patients undergoing cataract surgery, and the association between the two. PATIENTS AND METHODS: This was a retrospective observational case-control study, conducted in the Central District of Clalit Health Services (a district of the largest health maintenance organization in Israel). All Clalit members in the district older than 50 years who underwent cataract surgery from 2000 to 2007 (n=12,984) and 25,968 age- and sex-matched controls comprised the sample. Electronic medical records of all patients in the study were reviewed. The main outcome measure was the prevalence of osteoporosis and the odds ratio of having osteoporosis among cataract patients compared with controls. RESULTS: Demographically, 41.8% were men with a mean age of 68.7 ± 8.2 years. A logistic regression model for osteoporosis showed that age, female sex, higher socioeconomic class, smoking, chronic renal failure, hyperthyroidism, rheumatoid arthritis, inflammatory bowel diseases, and cataract are all associated with increased prevalence of osteoporosis. Obesity is a protective factor for osteoporosis. In all age-groups, osteoporosis was more prevalent in cataract patients than in the control group. CONCLUSION: Among other well-known risk factors, osteoporosis is associated with the presence of cataracts. Common pathophysiological associations with both conditions, such as calcium imbalance, hormonal abnormalities, and shared genetic predisposition, are discussed.
24194965 A marriage of two "Methusalem" drugs for the treatment of psoriasis?: Arguments for a pilo 2013 Apr 1 In this article we present arguments that the "antidiabetic" drug metformin could be useful as an add-on therapy to methotrexate for the treatment of psoriasis and, perhaps, for rheumatoid arthritis as well. Biochemical data suggest that both drugs may share a common cellular target, the AMP-activated protein kinase (AMPK). This enzyme is a master regulator of metabolism and controls a number of downstream targets, e.g., important for cellular growth or function in many tissues including T-lymphocytes. Clinical observations as well as experimental results argue for anti-inflammatory, antineoplastic and antiproliferative activities of metformin and a case-control study suggests that the drug reduces the risk for psoriasis. Patients with psoriasis have higher risk of metabolic syndrome, type 2 diabetes and cardiovascular mortality. Metformin has proven efficacy in the treatment of prediabetes and leads to a pronounced and sustained weight loss in overweight individuals. We expect that addition of metformin to methotrexate can lead to positive effects with respect to the PASI score, reduction of the weekly methotrexate dose and of elevated cardiovascular risk factors in patients with metabolic syndrome and psoriasis. For reasons explained later we suggest that only male, overweight patients are to be included in a pilot trial. On the other side of the coin are concerns that the gastrointestinal side effects of metformin are intolerable for patients under low dose, intermittent methotrexate therapy. Metformin has another side effect, namely interference with vitamin B12 and folate metabolism, leading to elevated homocysteine serum levels. As patients must receive folate supplementation and will be controlled with respect to their B12 status increased hematological toxicity is unlikely to result.
24064024 Behçet's syndrome: a critical digest of the 2012-2013 literature. 2013 May Recent work on the epidemiology of Behçet's syndrome confirm the previous contention that the prevalence increases from North to South and that the disease follows a more severe course in patients with an early age of onset, also when specifically studied in patients with eye and gastrointestinal involvement. Imputation analyses of genome wide association studies revealed new associations such as ERAP-1, CCR1-CCR3, KLRC4 and STAT4. Further work suggested that the BS associated variant of STAT4 is not related to the previously reported one associated with autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. The prognosis of eye involvement seems to have improved over the last decade with better visual acuity and less frequent severe complications in patients reported in the 2000s compared to the 1990s. Immunosuppresssives and corticosteroids were observed to improve the outcome of cardiac involvement in BS. Recurrence and complications were common in these patients when surgery was performed without immunosuppressives. The cognitive dysfunction in BS patients with neurological involvement seemed to be severely impaired and worse than that of multiple sclerosis patients, suggesting a more severe 'frontal'-executive dysfunction. Gastrointestinal involvement seemed to be brought to a remission in the majority of BS within 5 years, with about one fourth of the patients following a relapsing or chronic disease course. TNF-α inhibitors have become standard treatment for patients resistant to conventional immunosuppressives. Switching to another biologic can be effective when the first or even the second biologic agent fails or is stopped due to adverse events.
24164900 Therapeutic targeting of the Jak/STAT pathway. 2014 Jan Antibodies that block cytokine function provide a powerful therapeutic tool especially for the treatment of autoimmune diseases. Cytokines are a group of small hydrophilic glycoproteins that bind their receptors on the cell surface and subsequently activate intracellular signalling cascades, such as the JAK/STAT pathway. A bulk of evidence has demonstrated that genetic mutations in signalling molecules can cause immunodeficiencies and malignant cell growth. As a result, several drug companies have begun to develop therapeutics that inhibit the function of JAK tyrosine kinases. Currently, two JAK inhibitors, tofacitinib and ruxolitinib, are used in the clinic for treating rheumatoid arthritis and myeloproliferative diseases, respectively. Inhibiting JAK function has been shown to efficiently prevent the uncontrolled growth of cancerous cells and to harness overly active immune cells. In the future, other small molecule compounds are likely to come into clinical use, and intense work is ongoing to develop inhibitors that specifically target the constitutively active mutant JAKs. This MiniReview will summarize the basic features of the JAK/STAT pathway, its role in human disease and the therapeutic potential of JAK/STAT inhibitors.
24117827 Neutrophil migration: moving from zebrafish models to human autoimmunity. 2013 Nov There has been a resurgence of interest in the neutrophil's role in autoimmune disease. Classically considered an early responder that dies at the site of inflammation, new findings using live imaging of embryonic zebrafish and other modalities suggest that neutrophils can reverse migrate away from sites of inflammation. These 'inflammation-sensitized' neutrophils, as well as the neutrophil extracellular traps and other products made by neutrophils in general, may have many implications for autoimmunity. Here, we review what is known about the role of neutrophils in three different autoimmune diseases: rheumatoid arthritis, systemic lupus erythematosus, and small vessel vasculitis. We then highlight recent findings related to several cytoskeletal regulators that guide neutrophil recruitment including Lyn, Rac2, and SHIP. Finally, we discuss how our improved understanding of the molecules that control neutrophil chemotaxis may impact our knowledge of autoimmunity.
24090264 Targeting leukotriene B4 in inflammation. 2014 Jan INTRODUCTION: Leukotriene (LT) B(4) is a powerful proinflammatory lipid mediator and triggers adherence to the endothelium, activates and recruits leukocytes to the site of injury. When formed in excess, LTB(4) plays a pathogenic role and may sustain chronic inflammation in diseases such as asthma, rheumatoid arthritis, and inflammatory bowel disease. Recent investigations have also indicated that LTB(4) is involved in cardiovascular diseases. AREAS COVERED: As the 5-lipoxygenase pathway involves several discrete, tightly coupled, enzymes, which convert the substrate, 'step by step', into bioactive products, several different strategies have been used to target LTB(4) as a means to treat inflammation. Here, we discuss recent findings regarding the development of selective enzyme inhibitors and antagonists for LTB(4) receptors, as well as their application in preclinical and clinical studies. EXPERT OPINION: Components of the 5-lipoxygenase pathway have received considerable attention as candidate drug targets resulting in one new class of medications against asthma, that is, the antileukotrienes. However, efforts to specifically target LTB(4) have not yet been fruitful in the clinical setting, in spite of very promising preclinical data. Recently, crystal structures along with hitherto unknown functions of key enzymes in the leukotriene cascade have emerged, offering new opportunities for drug development and, with time, pharmacological intervention in LTB(4)-mediated pathologies.
24001128 Review article: biosimilars are the next generation of drugs for liver and gastrointestina 2013 Oct BACKGROUND: A biosimilar is a copy version of an approved original biological medicine whose data protection has expired. AIM: To provide an overview of the development of biosimilars worldwide. METHODS: Literature review of manufacturing processes of biosimilars, differences and similarities between biosimilars and the reference product, approval pathways for biosimilars, challenges in clinical trial study design and available data from clinical trials. RESULTS: Biosimilars have the same amino acid sequence and highly similar glycosylation patterns that overlap with the originator product. Both efficacy and toxicity are difficult to predict due to subtle molecular changes that might have profound effects on clinical efficacy, safety and immunogenicity. Their main advantage is related to cost savings. Direct evidence of safety and benefit from clinical trials, post-marketing pharmacoviligance and unequivocal identification of the product as a biosimilar are requirements before approval. Non-inferiority or equivalence trials are required by regulatory agencies. Over the past years, several biosimilars have been approved such as erythropoietin or growth factors. Recently, two monoclonal antibodies, Remsima and Inflectra, have been shown to be equivalent to infliximab (INX) in safety and efficacy in rheumatologic conditions. Interchangeability, automatic substitution and switching are key issues when treating patients with biosimilars in clinical practice. CONCLUSIONS: Biosimilars represent a new generation of drugs in liver and gastrointestinal diseases. On June 27, 2013, Hospira's Inflectra (INX) was the first biosimilar monoclonal antibody to receive positive opinion from European Medicines Agency's Committee for Medicinal Products for Human Use for rheumatoid arthritis, inflammatory bowel disease and plaque psoriasis.
23998445 The quest for better understanding of HLA-disease association: scenes from a road less tra 2013 Sep Dozens of human diseases and health traits are significantly more common among individuals carrying particular human leukocyte antigens (HLA) alleles. The underlying mechanism of this phenomenon, commonly referred to as "HLA-disease association," has been the subject of a decades-long debate. The prevailing hypotheses implicate an auto-aggressive immune response due to aberrant presentation of self-, self-mimicking-, or altered self-antigens by HLA molecules. However, the identity of such putative antigens remains elusive in the vast majority of HLA-associated diseases. Moreover, antigen presentation-based hypotheses are difficult to reconcile with epidemiologic data and functional characteristics of HLA molecules. To provide better answers to these inconsistencies an alternative theory involving allele-based, antigen presentation-independent mechanism is proposed here. Recent research findings in rheumatoid arthritis, an emblematic HLA-associated disease, lend support to the proposed theory.