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ID PMID Title PublicationDate abstract
21283107 Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. 2011 Feb Recent advances in our understanding of the pathogenesis of the Philadelphia chromosome-negative myeloproliferative neoplasms, polycythaemia vera, essential thrombocythaemia and myelofibrosis have led to the identification of the mutation V617F in Janus kinase (JAK) as a potential therapeutic target. This information has prompted the development of ATP-competitive JAK2 inhibitors. Therapy with JAK2 inhibitors may induce rapid and marked reductions in spleen size and can lead to remarkable improvements in constitutional symptoms and overall quality of life. Because JAKs are involved in the pathogenesis of inflammatory and immune-mediated disorders, JAK inhibitors are also being tested in clinical trials in patients with rheumatoid arthritis and psoriasis, as well as for the treatment of other autoimmune diseases and for the prevention of allograft rejection. Preliminary results indicate that these agents hold great promise for the treatment of JAK-driven disorders.
21233039 Modified kinematic technique for measuring pathological hyperextension and hypermobility o 2011 May Dynamic finger joint motion is difficult to measure using optical motion analysis techniques due to the limited surface area allowed for adequate marker placement. This paper describes an extension of a previously validated kinematic measurement technique using a reduced surface marker set and outlines the required calculations based on a specific surface marker placement to calculate flexion/extension and hyperextension of the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints. The modified technique has been assessed for accuracy using a series of static reference frames (absolute residual error = ±3.7°, cross correlation between new method and reference frames; r=0.99). The method was then applied to a small group of participants with rheumatoid arthritis (seven females, one male; mean age = 62.8 years ± 12.04) and illustrated congruent strategies of movement for a participant and a large range of finger joint movement over the sample (5.8-71.1°, smallest to largest active range of motion). This method used alongside the previous paper provides a comprehensive, validated method for calculating 3-D wrist, hand, fingers, and thumb kinematics to date and provides a valuable measurement tool for clinical research.
21158977 The pulse of inflammation: heart rate variability, the cholinergic anti-inflammatory pathw 2011 Jan Biological therapeutics targeting TNF, IL-1 and IL-6 are widely used for treatment of rheumatoid arthritis, inflammatory bowel disease and a growing list of other syndromes, often with remarkable success. Now advances in neuroscience have collided with this therapeutic approach, perhaps rendering possible the development of nerve stimulators to inhibit cytokines. Action potentials transmitted in the vagus nerve culminate in the release of acetylcholine that blocks cytokine production by cells expressing acetylcholine receptors. The molecular mechanism of this cholinergic anti-inflammatory pathway is attributable to signal transduction by the nicotinic alpha 7 acetylcholine receptor subunit, a regulator of the intracellular signals that control cytokine transcription and translation. Favourable preclinical data support the possibility that nerve stimulators may be added to the future therapeutic armamentarium, possibly replacing some drugs to inhibit cytokines.
21098742 Pregnancy outcomes after maternal exposure to rituximab. 2011 Feb 3 Rituximab is a chimeric anti-CD20 monoclonal B cell-depleting antibody indicated for certain hematologic malignancies and active rheumatoid arthritis with inadequate response to tumor necrosis factor antagonists. Despite counseling to avoid pregnancy, women may inadvertently become pregnant during or after rituximab treatment. Using the rituximab global drug safety database, we identified 231 pregnancies associated with maternal rituximab exposure. Maternal indications included lymphoma, autoimmune cytopenias, and other autoimmune diseases. Most cases were confounded by concomitant use of potentially teratogenic medications and severe underlying disease. Of 153 pregnancies with known outcomes, 90 resulted in live births. Twenty-two infants were born prematurely; with one neonatal death at 6 weeks. Eleven neonates had hematologic abnormalities; none had corresponding infections. Four neonatal infections were reported (fever, bronchiolitis, cytomegalovirus hepatitis, and chorioamnionitis). Two congenital malformations were identified: clubfoot in one twin, and cardiac malformation in a singleton birth. One maternal death from pre-existing autoimmune thrombocytopenia occurred. Although few congenital malformations or neonatal infections were seen among exposed neonates, women should continue to be counseled to avoid pregnancy for ≤ 12 months after rituximab exposure; however, inadvertent pregnancy does occasionally occur. Practitioners are encouraged to report complete information to regulatory authorities for all pregnancies with suspected or known exposure to rituximab.
20805369 Polymorphisms at 16p13 are associated with systemic lupus erythematosus in the Chinese pop 2011 Jan BACKGROUND: Chromosomal region 16p13 has been reported to harbour variants associated with several autoimmune diseases, including type I diabetes, rheumatoid arthritis and multiple sclerosis. OBJECTIVE: To test whether variants in the 16p13 region are also associated with systemic lupus erythematosus (SLE) by performing a candidate locus study in the Chinese Han population. METHODS: Tag single nucleotide polymorphisms (SNPs) encompassing 50 kb upstream and downstream of the 250 kb linkage disequilibrium block, previously implicated in several autoimmune diseases, were analysed in 1047 patients with SLE and 1205 controls. The SNP showing the strongest association with SLE was then replicated in an independent cohort of 1643 cases and 5930 controls. RESULTS AND CONCLUSIONS: The association between SNP rs12599402 and SLE reached the genome-wide significance level (p<5 × 10⁻⁸). The SNP was likely to tag the same functional variant as previously reported in European populations. The results suggested that the chromosomal region at 16p13 contains common susceptibility genes for different immune-mediated disorders.
19890635 Necrotizing fasciitis in a patient with overlap syndrome of systemic sclerosis and systemi 2011 Jul Necrotizing fasciitis (NF) is an uncommon destructive disease and fatal infection of the subcutaneous tissue. The literature includes a limited number of NF cases in rheumatic disease such as rheumatoid arthritis and systemic lupus erythematosus (SLE). We report a 40-year-old patient who had complicated with NF during treatment with corticosteroid and azathioprine for overlap syndrome of systemic sclerosis and SLE. She underwent urgent surgical debridement and internal drainage with antibiotics and had complete recovery from NF. To our knowledge, this is the first case of NF developed in a patient of overlap syndrome with diffuse type of systemic sclerosis and SLE and suggests that NF can be a very rare cutaneous manifestation of this disease.
24527153 Calciphylaxis: a review. 2010 Dec Human calciphylaxis reflects a form of severe tissue compromise attributable to a unique microangiopathy that combines features of vascular thrombotic occlusion with endoluminal calcification. While most frequently described in patients with renal failure, it is seen in other settings, such as multiple myeloma; polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome; cirrhosis; and rheumatoid arthritis. Although most commonly involving the skin, calciphylaxis can affect other organs including the heart and gastrointestinal tract, in which cases it falls under the appellation of systemic calciphylaxis. There are cases in which the main pathology is one of endovascular thrombosis of the vessels of the fat without discernible calcification or one manifesting a pseudoangiosarcomatous pattern, hence adding to the histomorphologic spectrum of calciphylaxis. A variety of factors contribute to this severe occlusive microangiopathy, including an underlying procoagulant state and ectopic neo-osteogenesis of the microvasculature through varied mechanisms, including increased osteopontin production by vascular smooth muscle or reduced synthesis of fetuin and GLA matrix protein, important inhibitors of ectopic neo-osteogenesis. Certain factors adversely affect outcome, including truncal and genital involvement and systemic forms of calciphylaxis. With a better understanding of its pathophysiology, more-effective therapies, such as sodium thiosulfate and biphosphanates to reduce reactive oxygen species and receptor activator of nuclear factor κβ-mediated nuclear factor κβ activity, respectively, are being developed.
20099082 Lubricin: a novel potential biotherapeutic approaches for the treatment of osteoarthritis. 2011 Jun Osteoarthritis (OA) is a multi-factor disorder of sinovial joints, which characterized by escalated degeneration and loss of articular cartilage. Treatment of OA is a critical unmet need in medicine for regeneration of damaged articular cartilage in elderly. On the other hand, lubricin, a glycoprotein specifically synthesized by chondrocytes located at the surface of articular cartilage, has been shown to provide boundary lubrication of congruent articular surfaces under conditions of high contact pressure and near zero sliding speed. Lubrication of these surfaces is critical to normal joint function, while different gene expressions of lubricin had been found in the synovium of rheumatoid arthritis (RA) and OA. Moreover, mutations or lacking of lubricin gene have been shown to link to the joint disease such as camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP), synovial hyperplasia and failure of joint function, suggesting an important role of lubricin in the pathogenesis of these joint disease. Recent studies demonstrate that administration with recombinant lubricin in the joint cavity would be effective in the prevention of cartilage degeneration in animal OA models. Therefore, a treatment with lubricin which would protect cartilage in vivo would be desirable. This article reviews recent findings with regard to the possible role of lubricin in the progression of OA, and further discusses lubricin as a novel potential biotherapeutic approaches for the treatment of OA.
23226610 Orbital apex syndrome due to aspergillosis with subsequent fatal subarachnoid hemorrhage. 2012 BACKGROUND: Orbital apex syndrome has been described previously as a syndrome involving damage to the oculomotor nerve (III), trochlear nerve (IV), abducens nerve (VI), and ophthalmic branch of the trigeminal nerve (V1), in association with optic nerve dysfunction. It may be caused by inflammatory, infectious, neoplastic, iatrogenic, or vascular processes. CASE DESCRIPTION: A 73-year-old female having hypertension and rheumatoid arthritis stage 4 under long-term corticosteroid therapy presented to us with the right side orbital apex syndrome. Her magnetic resonance imaging (MRI) of orbit showed progression of a lesion at the right orbital apex and adjacent right superior orbital fissure with mild extension to the right posterior ethmoid sinus. She underwent endoscopic endonasal transethmoid approach with the removal of the lesion. The pathology showed a picture of fungal infection and the culture of the specimen proved Aspergillus fumigatus. Her postoperative course was smooth until 5 days after surgery, when she suffered a massive spontaneous subarachnoid hemorrhage resulting from a ruptured aneurysm, which was proven by computed tomography angiography (CTA) of brain. Unfortunately, she expired due to central failure. CONCLUSION: In cases of immunocompromised patients having orbital apex syndrome, fungal infection should be kept in mind. One of the most lethal but rare sequels of CNS fungal infection is intracranial aneurysms. Early diagnosis and radical resection, combined with antifungal medications is the key to save this particular group of patients.
23151054 Rational design of highly selective spleen tyrosine kinase inhibitors. 2012 Dec 13 A novel approach to design selective spleen tyrosine kinase (Syk) inhibitors is described. Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of autoimmune diseases such as asthma, rheumatoid arthritis, and SLE. Fostamatinib, a Syk inhibitor that successfully completed phase II clinical trials, also exhibits some undesirable side effects. More selective Syk inhibitors could offer safer, alternative treatments. Through a systematic evaluation of the kinome, we identified Pro455 and Asn457 in the Syk ATP binding site as a rare combination among sequence aligned kinases and hypothesized that optimizing the interaction between them and a Syk inhibitor molecule would impart high selectivity for Syk over other kinases. We report the structure-guided identification of three series of selective spleen tyrosine kinase inhibitors that support our hypothesis and offer useful guidance to other researchers in the field.
23118496 α-Enolase, a multifunctional protein: its role on pathophysiological situations. 2012 α-Enolase is a key glycolytic enzyme in the cytoplasm of prokaryotic and eukaryotic cells and is considered a multifunctional protein. α-enolase is expressed on the surface of several cell types, where it acts as a plasminogen receptor, concentrating proteolytic plasmin activity on the cell surface. In addition to glycolytic enzyme and plasminogen receptor functions, α-Enolase appears to have other cellular functions and subcellular localizations that are distinct from its well-established function in glycolysis. Furthermore, differential expression of α-enolase has been related to several pathologies, such as cancer, Alzheimer's disease, and rheumatoid arthritis, among others. We have identified α-enolase as a plasminogen receptor in several cell types. In particular, we have analyzed its role in myogenesis, as an example of extracellular remodelling process. We have shown that α-enolase is expressed on the cell surface of differentiating myocytes, and that inhibitors of α-enolase/plasminogen binding block myogenic fusion in vitro and skeletal muscle regeneration in mice. α-Enolase could be considered as a marker of pathological stress in a high number of diseases, performing several of its multiple functions, mainly as plasminogen receptor. This paper is focused on the multiple roles of the α-enolase/plasminogen axis, related to several pathologies.
22796801 Biologic therapies: lessons from multiple sclerosis. 2012 New evidence points to a possible association of multiple sclerosis (MS) with IBD. Tumour necrosis factor (TNF) is involved in the pathogenesis of MS. Paradoxically, administration of anti-TNF monoclonal antibodies to IBD patients has led to exacerbation of MS or triggered demyelination. TNF receptor 1 (TNFR1) mediates demyelination and TNFR2 mediates remyelination, suggesting that a more selective approach to TNF antagonism may be required for an anti-TNF strategy to be effective in MS. Conversely, interferon treatment for MS may worsen IBD. Anti-lymphocyte trafficking strategies such as alpha4 integrin blockers are effective in both these diseases. Recent advances in small molecule development in this area may provide further effective therapies. Common inflammatory cytokine and signaling pathways may be shared between MS and IBD, such as TNF, interleukin (IL)-12/23, IL-17, CD40 and STAT3. However, in contrast to Crohn's disease, ustekinumab has not shown efficacy in MS. Vitamin D deficiency is a hot topic in both diseases. Several drugs developed for MS, e.g. glatiramer acetate, are also being studied in IBDs. As in rheumatoid arthritis, MS also serves as an example of a chronic relapsing inflammatory disease where disease modification is the goal of treatment based on objective evidence derived from imaging, in turn providing examples of how to conduct IBD studies in future.
22777068 [New kinase inhibitors]. 2012 Aug Treatment of rheumatoid arthritis (RA) has dramatically changed during the last 15 years. A limited number of conventional disease-modifying antirheumatic drugs (DMARD) in combination with non-steroid anti-inflammatory drugs (NSAID) and corticosteroids are facing a variety of biologics that are increasingly being used. Because of the high costs of biologics as well as the necessity for subcutaneous or intravenous administration, there is currently a growing interest in new and potent oral compounds such as the small molecules. Inflammatory pathways and mechanisms in signal transduction have been characterized in detail. Instead of neutralizing the action of a proinflammatory cytokine by antagonizing its biologic effect by an antibody, these small molecules interfere with the intracellular pathways of the inflammatory cascade. Intracellular kinases are among these enzymes which are crucially involved in intracellular signal transduction. Kinase inhibitors have been successfully used within the last few years in the treatment of various hematological malignancies, such as imatinib in patients with chronic myeloid leukemia. More recently, the Janus kinase (JAK) inhibitor tofacitinib has been evaluated as a potential new treatment option in RA and is awaiting approval. While an overview about JAK inhibition will be given elsewhere, other inhibitors such as spleen tyrosine kinase (Syk) inhibitor, mitogen-activated protein kinase (MAPK) inhibitor and Bruton's tyrosine kinase (Btk) inhibitor are currently in preclinical and clinical development.
22743033 Overlap connective tissue disease syndromes. 2013 Jan Overlap Syndromes (OSs) have been defined as entities satisfying classification criteria of at least two connective tissue diseases (CTDs) occurring at the same or at different times in the same patient. CTDs include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), polymyositis/dermatomyositis (PDM), and Sjögren syndrome (SS). Every combination between these disorders has been reported. In some OS a specific autoantibody has been indentified, supporting the hypothesis that these syndromes are not a mere association of two or more CTD in the same patient, but a well defined clinical entity with specific clinical characteristics. As an example, anti-t-RNA synthetase syndrome is characterized by the presence of anti-t-RNA synthetase antibodies. Notably, clinical manifestations observed in OS may be different from those observed in the single CTD. The treatment of OS is mainly based on the use of corticosteroids and immunosuppressants. Biologic drugs, i.e. anti-TNFα or anti-CD20 monoclonal antibodies, have been recently introduced as alternative treatments in refractory cases. Moreover, there are some concerns with the use of anti-TNF agents in patients with systemic autoimmune diseases due to the risk of triggering disease exacerbations. In this paper the most frequent OS are described with a special focus on the specific immunologic and clinical aspects. Furthermore, some personal data on anti-t-RNA synthetase syndrome and rhupus syndrome are reported.
22743032 Autoimmune diseases in the intensive care unit. An update. 2013 Jan Autoimmune diseases (ADs) are a challenge at the intensive care unit. The management of patients with these diseases in the critical care setting has improved over time since there are new and more aggressive alternatives to treat and diagnose them. We aimed to review the current causes of admission, clinical features, outcomes and variables associated with mortality of patients with ADs admitted to the intensive care unit (ICU). International classification criteria for ADs were used to include patients. Search was done through PubMed, SCOPUS, SciELO, and LILACS databases up to December of 2011.Twenty-nine case series and forty-one case reports were analyzed after quality assessment. Respiratory involvement was the leading cause of admission. Systemic lupus erythematosus (SLE) (33.5% of reported patients), rheumatoid arthritis (25%) and systemic vasculitis (15%) were the most frequent ADs in patients admitted to the ICU in the last decade. Mortality ranged from 17% to 55% in case series including all ADs, but in the ones that only included patients with a specific AD, such as SLE, it reached up to 79%. High APACHE score, multi-organ dysfunction, older age and cytopenia were the most reported variables associated with mortality. In conclusion, ADs should always be considered in patients with life threatening conditions that warrant critical care. Variables influencing mortality should be promptly identified in order to improve the patients' outcomes.
22588418 Minocycline-induced black bone disease encountered during total knee arthroplasty. 2012 May Finding discolored bone intraoperatively can be confusing and concerning to orthopedic surgeons. Multiple causes of pigmented bone exist, including ochronosis, metabolic bone diseases, metal deposits, sequestrum, metastatic disease, and minocycline use. Bone quality is an important consideration in intraoperative decision making with respect to components and fixation options in total joint arthroplasty. Abnormal bone encountered in routine arthroplasty can raise concerns over the integrity and healing potential of the bone when the etiology is uncertain.Minocycline is a drug routinely used for the treatment of acne, rosacea, and rheumatoid arthritis. Pigmentation is a commonly recognized adverse reaction associated with most of the drugs in the tetracycline family, affecting the skin, nails, teeth, oral mucosa, bones in the oral cavity, ocular structures, cartilage, thyroid, and other visceral structures.This article describes a case of pigmented bone secondary to minocycline use in a 55-year-old woman undergoing total knee arthroplasty. This entity has rarely been documented in the orthopedic literature; however, orthopedic surgeons should be aware of this side effect secondary to the widespread use of minocycline. Questions concerning the effect of minocycline on bone metabolism and structural integrity have yet to be fully answered, but an understanding and recognition of the entity will help guide surgeons with intraoperative decision making.
22562025 Protein modification by oxidized phospholipids and hydrolytically released lipid electroph 2012 Oct Oxygen is essential for the growth and function of mammalian cells. However, imbalances in oxygen or abnormalities in the ability of a cell to respond to oxygen levels can result in oxidative stress. Oxidative stress plays an important role in a number of diseases including atherosclerosis, rheumatoid arthritis, cancer, neurodegenerative diseases and asthma. When membrane lipids are exposed to high levels of oxygen or derived oxidants, they undergo lipid peroxidation to generate oxidized phospholipids (oxPL). Continual exposure to oxidants and decomposition of oxPL results in the formation of reactive electrophiles, such as 4-hydroxy-2-nonenal (HNE). Reactive lipid electrophiles have been shown to covalently modify DNA and proteins. Furthermore, exposure of cells to lipid electrophiles results in the activation of cytoprotective signaling pathways in order to promote cell survival and recovery from oxidant stress. However, if not properly managed by cellular detoxification mechanisms, the continual exposure of cells to electrophiles results in cytotoxicity. The following perspective will discuss the biological importance of lipid electrophile protein adducts including current strategies employed to identify and isolate protein adducts of lipid electrophiles as well as approaches to define cellular signaling mechanisms altered upon exposure to electrophiles. This article is part of a Special Issue entitled: Oxidized phospholipids-their properties and interactions with proteins.
22500176 Risk of orthopedic surgical site infections in patients with rheumatoid arthritis treated 2012 Introduction. International guidelines recommend interruption of anti-TNF medications in the perioperative period, but there are no randomized trials to support such recommendation. Objectives. To study literature evidence assessing the risk of surgical site infections in orthopedic surgery patients with RA using anti-TNF drugs, compared to untreated patients or those using conventional DMARD. Methods. Systematic review of cohort studies is concerning surgical site infections in orthopedic procedures in patients with RA. Results. Three studies were selected. Only one was considered of high-quality, albeit with low statistical power. The review resulted in inconclusive data, since the best quality study showed no significant differences between groups, while others showed increased risk of infections in patients using anti-TNF medications. Conclusion. It is unclear whether patients with RA using anti-TNF medications are at increased risk of surgical site infections. Randomized controlled trials or new high quality observational studies are needed to clarify the issue.
22404847 Synthesis and biological evaluation of N-aryl-4-aryl-1,3-thiazole-2-amine derivatives as d 2012 Jul Biological evaluation of N-aryl-4-aryl-1,3-thiazole-2-amine derivatives was examined for anti-inflammatory activity in in vitro and in vivo assays. The thiazole compounds showed direct inhibition of 5-lipoxygenase (LOX) that is a key enzyme of leukotrienes synthesis and involved in the inflammation-related diseases, including asthma and rheumatoid arthritis. To optimize biological activity, we synthesized 1,3-thiazole-2-amine derivatives and investigated for structure and activity relationship. Especially, N-(3,5-dimethylphenyl)-4-(4-chlorophenyl)-1,3-thiazole-2-amine was shown to have a potent anti-inflammatory activity as a 5-LOX inhibitor.
22306730 Ulcerative colitis from patients' viewpoint: a review of two Internet surveys. 2012 Jan Ulcerative colitis negatively impacts patients' quality of life, but little is known about which aspects of patients' lives are affected, how patients' perceptions compare with patients with other chronic conditions, and how these perceptions compare with those of gastroenterologists. This review discusses two recent Internet surveys: (1) the Ulcerative Colitis: New Observations on Remission Management And Lifestyle (UC:NORMAL) and (2) the Crohn's and Colitis Foundation of America studies. The surveys revealed that the major impact ulcerative colitis has on patients includes frequent disease manifestations, a substantial psychological burden, and disruption to daily activities. This was more evident in patients with ulcerative colitis than those with migraine, asthma, or rheumatoid arthritis. Physicians' perceptions were considerably different from those of patients, as physicians believed that the disease had a lesser impact on patient quality of life. Furthermore, patients and physicians also identified nonadherence to prescribed medication as a major concern in the treatment of ulcerative colitis. Improved communication and education is needed to address nonadherence and poor health related quality of life in patients living with ulcerative colitis. The influence of Advanced Practice Registered Nurses on physicians, nurses, and patients may help improve adherence and long-term disease outcomes, including patients' health related quality of life. The nurse practitioner, working with both patients who have ulcerative colitis and the physicians who care for these patients, is uniquely placed to address these needs.