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ID PMID Title PublicationDate abstract
22046967 Risk of infections in bronchiectasis during disease-modifying treatment and biologics for 2011 Nov 2 BACKGROUND: Bronchiectasis is frequently associated (up to 30%) with chronic inflammatory rheumatic diseases and leads to lower respiratory tract infections. Data are lacking on the risk of lower respiratory tract infections in patients treated with biologic agents. METHODS: Monocenter, retrospective systematic study of all patients with a chronic inflammatory rheumatic disease and concomitant bronchiectasis, seen between 2000 and 2009. Univariate and multivariate analyses were performed to evidence predictive factors of the number of infectious respiratory events. RESULTS: 47 patients were included (mean age 64.1±9.1 years, 33 (70.2%) women), with a mean follow-up per patient of 4.3±3.1 years. Rheumatoid arthritis was the main rheumatic disease (90.1%). The mean number of infectious events was 0.8±1.0 event per patient-year. The factors predicting infections were the type of treatment (biologic vs. non biologic disease-modifying treatments), with an odds ratio of 8.7 (95% confidence interval: 1.7-43.4) and sputum colonization by any bacteria (odds ratio 7.4, 2.0-26.8). In multivariate analysis, both factors were independently predictive of infections. CONCLUSION: Lower respiratory tract infectious events are frequent among patients receiving biologics for chronic inflammatory rheumatic disease associated with bronchiectasis. Biologic treatment and pre-existing sputum colonization are independent risk factors of infection occurrence.
22013498 Resveratrol regulates antioxidant status, inhibits cytokine expression and restricts apopt 2011 Recent studies indicate the chemopreventive role of resveratrol in many animal models like ischemia, rheumatoid arthritis, human cancer, and diabetes. The present study was designed to investigate the chemopreventive potential of resveratrol in rat hepatic injury model by carbon tetrachloride. Male Wistar rats were treated with carbon tetrachloride (0.4 g/kg body weight) intraperitoneally daily for 8 weeks. Resveratrol (100 mg/kg, 200 mg/kg body weight) was given orally from first day until the last day of experiment. The investigation assesses the effect of resveratrol on morphological, oxidative status, histopathological, immunohistochemical, and apoptotic analysis in carbon tetrachloride-challenged liver tissue. The study indicated that the inflammatory cytokines TNF-α and IL-6 were profoundly expressed in experimental rats, whereas resveratrol decreases the immunopositivity of TNF-α and IL-6 and restored the altered architectural structure of challenged hepatic tissue. Resveratrol also protects liver cells by suppressing oxidative stress and apoptosis.
21873529 Mycophenolic acid differentially impacts B cell function depending on the stage of differe 2011 Oct 1 Production of pathogenic Abs contributes to disease progression in many autoimmune disorders. The immunosuppressant agent mycophenolic acid (MPA) has shown clinical efficacy for patients with autoimmunity. The goal of these studies was to elucidate the mechanisms of action of MPA on B cells isolated from healthy individuals and autoimmune patients. In this study, we show that MPA significantly inhibited both proliferation and differentiation of primary human B cells stimulated under various conditions. Importantly, MPA did not globally suppress B cell responsiveness or simply induce cell death, but rather selectively inhibited early activation events and arrested cells in the G0/G1 phase of the cell cycle. Furthermore, MPA blocked expansion of both naive and memory B cells and prevented plasma cell (PC) differentiation and Ab production from healthy controls and individuals with rheumatoid arthritis. Finally, whereas MPA potently suppressed Ig secretion from activated primary B cells, terminally differentiated PCs were not susceptible to inhibition by MPA. The target of MPA, IMPDH2, was found to be downregulated in PCs, likely explaining the resistance of these cells to MPA. These results suggest that MPA provides benefit in settings of autoimmunity by directly preventing activation and PC differentiation of B cells; however, MPA is unlikely to impact autoantibody production by preexisting, long-lived PCs.
21861807 Recent developments in the medicinal chemistry and therapeutic potential of dihydroorotate 2011 Oct Dihydroorotate dehydrogenase (DHODH) is a flavin-dependent mitochondrial enzyme that catalyzes fourth reaction of pyrimidine de-novo synthesis. Pyrimidine bases are essential for cellular metabolism and cell growth, and are considered as important precursors used in DNA (thymine and cytosine), RNA (uracil and cytosine), glycoproteins and phospholipids biosynthesis. The significance of pyrimidines biosynthesis in DNA and RNA makes them ideal targets for pharmacological intervention. Inhibitors of DHODH have proven efficacy for the treatment of malaria, autoimmune diseases, cancer, rheumatoid arthritis and psoriasis. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) represents an important target for the treatment of malaria. Many of the clinically relevant anti-tumor and immunosuppressive drugs target human dihydroorotate dehydrogenase (hDHODH), and the two most promising drugs of such kinds are brequinar (antitumor and immunosuppressive) and leflunomide (immunosuppressive). X-ray crystal structures of DHODH in complex with inhibitors reveal common binding region shared by each inhibitor. A number of compounds are identified by high-throughput screening (HTS) of chemical libraries and structure-based computational approaches as selective DHODH inhibitors. Based upon the understanding of molecular interaction of DHODH inhibitors with binding site, some of the common structural features are identified like ability of compounds to interact with ubiquinone (CoQ) binding site and substituents linked to a variety of heterocyclic and heteroaromatic rings responsible for H-bonding with binding site. These findings provide new approaches to design DHODH inhibitors and highlights DHODH as a target for chemotherapeutics. This review is mainly focused on the recent developments in the medicinal chemistry and therapeutic potential of DHODH inhibitors as a target for drug discovery.
21844919 The London position statement of the World Congress of Gastroenterology on Biological Ther 2011 Sep This paper in the series from the World Congress of Gastroenterology addresses the safety and immunogenicity of biological therapy. The safety profile in randomized controlled studies of all biological agents in Crohn's disease (CD) and ulcerative colitis has been generally favorable, but a small percentage of patients experience severe side effects on biological therapy, including pneumonia, tuberculosis, lymphoma, demyelination, drug-induced lupus, or hepatotoxicity. Although there is unequivocal evidence of an increased risk of serious infection among patients with rheumatoid arthritis treated with anti-tumor necrosis factor therapy, the evidence is less clear in CD. The risk of infection may be increased by combination therapy with steroids and/or immunomodulators. There is a specific risk of the rare γ δ hepatosplenic lymphoma that appears to have a predeliction for young males on combination therapy. The α4 integrin antagonist natalizumab also carries a specific risk of progressive multifocal leucoencephalopathy and reactivation of JC virus infection. The immunogenicity of biological therapy is complex: all agents are potentially immunogenic and this can be reduced by combination with immunomodulators. This may enhance both therapeutic efficacy and the risk of infection or malignancy, so the balance of risk and benefit must be judged for individual patients.
21504485 Treatment of plaque-type psoriasis with oral CF101: data from an exploratory randomized ph 2012 Mar AIMS: CF101 demonstrated a marked anti-inflammatory effect in Phase 2 studies conducted in patients with rheumatoid arthritis and dry eye syndrome. The aim of this study was to evaluate the safety and efficacy of CF101 for the treatment of patients with moderate to severe plaque-type psoriasis. MATERIALS AND METHODS: This was a phase 2, multicentre, randomized, double-blind, dose-ranging, placebo-controlled study. Seventy five patients with moderate to severe plaque-type psoriasis were enrolled, randomized and treated with CF101 (1, 2, or 4 mg) or placebo administered orally twice daily for 12 weeks. Safety and change from base line of Psoriasis Area and Severity Index (PASI) score and physician's global assessment (PGA) score over 12 weeks. RESULTS: In the 2 mg CF101-treated group, a progressive improvement in the mean change from baseline in the PASI score vs. placebo throughout the study period was observed, with a statistically significant difference on weeks 8 and 12 (P = 0.047; P = 0.031, respectively). In this group, 35.3% of the patients achieved PASI ≥ 50 response, and 23.5% of the patients achieved a PGA score of 0 or 1. CF101 was safe and well tolerated. CONCLUSIONS: CF101 was well tolerated and demonstrated clear evidence of efficacy in patients with moderate to severe plaque psoriasis.
21487807 Elevated serum level of interleukin-32α in the patients with myasthenia gravis. 2011 Oct A new cytokine, interleukin-32 (IL-32), has been implicated in the pro-inflammatory immune responses in several autoimmune disorders, such as rheumatoid arthritis and inflammatory bowel diseases. Myasthenia gravis (MG) is a well-characterized autoimmune disease directed at the postsynaptic acetylcholine receptor (AChR) or end plate of the neuromuscular junction. IL-32 is a cytokine that induces tumor necrosis factor (TNF)-α, IL-6, IL-1β, and chemokine. IL-6, TNF-α, and IL-2 are related to the pathogenesis and immunoregulation of MG. The gene expression of IL-32 is increased in human natural killer (NK) cells and T lymphocytes when stimulated by IL-2 or mitogen. NK cells influence the development of experimental autoimmune MG (EAMG) and possibly MG. The aim of this study was to examine whether IL-32α levels are increased in patients with MG and to investigate the relationship between IL-32α levels and disease activity in human MG. Serum IL-32α levels were significantly higher in the MG patients (p = 0.03): 460.07 ± 192.30 pg/mL in MG patients and 248.45 ± 188.42 pg/mL in the healthy control group. Although there was no significant statistical difference, serum IL-32α levels of patients with both anti-AChR binding and blocking antibodies trended to be higher than those without either antibodies (521.56 ± 212.92 pg/mL vs. 339.52 ± 182.78 pg/mL, p = 0.16). IL-32α serum levels tended to decrease with clinical improvement in generalized MG. This study suggests the possibility that IL-32 might contribute to MG pathogenesis or immunoregulation.
21407167 Depression's multiple comorbidities explained by (neuro)inflammatory and oxidative & nitro 2011 There is now evidence that depression, as characterized by melancholic symptoms, anxiety, and fatigue and somatic (F&S) symptoms, is the clinical expression of peripheral cell-mediated activation, inflammation and induction of oxidative and nitrosative stress (IO&NS) pathways and of central microglial activation, decreased neurogenesis and increased apoptosis. This review gives an explanation for the multiple "co-morbidities" between depression and a large variety of a) brain disorders related to neurodegeneration, e.g. Alzheimer's, Parkinson's and Huntington's disease, multiple sclerosis and stroke; b) medical disorders, such as cardiovascular disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, inflammatory bowel disease, irritable bowel syndrome, leaky gut, diabetes type 1 and 2, obesity and the metabolic syndrome, and HIV infection; and c) conditions, such as hemodialysis, interferon-α-based immunotherapy, the postnatal period and psychosocial stressors. The common denominator of all those disorders/conditions is the presence of microglial activation and/or activation of peripheral IO&NS pathways. There is evidence that shared peripheral and / or central IO&NS pathways underpin the pathophysiology of depression and the previously mentioned disorders and that activation of these IO&NS pathways contributes to shared risk. The IO&NS pathways function as a smoke sensor that detect threats in the peripheral and central parts of the body and signal these threats as melancholic, anxiety, and fatigue and somatic (F&S) symptoms. The presence of concomitant depression is strongly associated with a lower quality of life and increased morbidity and mortality in medical disorders. This may be explained since depression contributes to increased (neuro)inflammatory burden and may therefore drive the inflammatory and degenerative progression. It is concluded that the activation of peripheral and / or central IO&NS pathways may explain the co-occurrence of depression with the above disorders. This shows that depression belongs to the spectrum of inflammatory and degenerative disorders.
21362757 Healthcare costs of inflammatory myopathies. 2011 May OBJECTIVE: Little information exists regarding the economic burden related to inflammatory myopathies. Our objective was to estimate health services costs in a large, unselected, population-based sample of patients with inflammatory myopathies. METHODS: We identified subjects with polymyositis and dermatomyositis from administrative healthcare databases (covering all beneficiaries, about 7.5 million) in Quebec province, Canada. Average estimates of health services costs (physician visits, diagnostic tests and procedures, outpatient surgeries and procedures, acute care hospitalizations) for 2003 were calculated by multiplying health service use levels by the appropriate unit prices, determined from government fee schedules and other sources. Multiple linear regression analyses were performed to establish whether specific factors (age, sex, disease duration, region of residence, socioeconomic status, type of myositis, disease severity) were associated with cost. RESULTS: We identified 1102 subjects with inflammatory myopathy from January 1, 1989, to January 1, 2003. About two-thirds were women (68.9%); average age at case ascertainment was 57.4 years (SD 18.4). The average cost of all reimbursed health services, in 2008 Canadian dollars, was $4099 per patient (SD $9639). Costs increased with age, and were highest early in the disease course. Greater disease severity (defined as the need for prior hospitalization for myositis) was also a strong predictor of both physician costs and total costs. CONCLUSION: These results indicate significant economic burden related to inflammatory myopathies, with important demographic predictors. Our estimates suggest that the health services costs in inflammatory myopathies may equal, or exceed, those of other serious diseases, such as rheumatoid arthritis and systemic sclerosis.
21258774 [Long-term results in total knee arthroplasty. A meta-analysis of revision rates and funct 2011 Jul BACKGROUND: Total knee arthroplasty (TKA) is one of the most common procedures in orthopedic surgery and clinical success can be characterized by the revision rate and improvement of function. To quantify both characteristics two independent meta-analyses have been performed. MATERIALS AND METHODS: A search in Medline provided a total of 96 studies on revision rates and 63 studies with functional results with a minimum follow-up of 5 years. RESULTS: A total of 911 revisions among 20,873 TKAs were identified corresponding to a meta-revision rate of 4.4% after a mean follow-up of 10.7 years. Most common causes for revision were aseptic loosening (31%), infection (23%), polyethylene wear (16%) and patellar problems (14%). Revision rates were higher in younger patients (7.0% <60 years at time of operation, 5.0% between 60 to 70 years and 2.2% >70 years), after cementless TKA (8.3% cementless versus 3.6% cemented) and in studies with a higher rate of patients with rheumatoid arthritis. The second meta-analysis revealed a meta-improvement based on the Knee Society Knee Score of 51.3%, for the Knee Society Function Score of 30.6%, for the Hospital for Special Surgery Score of 36.1% and for the New Jersey Orthopedic Hospital Knee Evaluation System of 33.6%. CONCLUSION: TKA is a successful treatment for osteoarthritis of the knee with an expectable revision rate of less than 5% within 10 years and a long-lasting functional improvement of more than 30% in any assessment score.
21219637 Risk of venous thromboembolism in people admitted to hospital with selected immune-mediate 2011 Jan 10 BACKGROUND: Venous thromboembolism (VTE) is a common complication during and after a hospital admission. Although it is mainly considered a complication of surgery, it often occurs in people who have not undergone surgery, with recent evidence suggesting that immune-mediated diseases may play a role in VTE risk. We, therefore, decided to study the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in people admitted to hospital with a range of immune-mediated diseases. METHODS: We analysed databases of linked statistical records of hospital admissions and death certificates for the Oxford Record Linkage Study area (ORLS1:1968 to 1998 and ORLS2:1999 to 2008) and the whole of England (1999 to 2008). Rate ratios for VTE were determined, comparing immune-mediated disease cohorts with comparison cohorts. RESULTS: Significantly elevated risks of VTE were found, in all three populations studied, in people with a hospital record of admission for autoimmune haemolytic anaemia, chronic active hepatitis, dermatomyositis/polymyositis, type 1 diabetes mellitus, multiple sclerosis, myasthenia gravis, myxoedema, pemphigus/pemphigoid, polyarteritis nodosa, psoriasis, rheumatoid arthritis, Sjogren's syndrome, and systemic lupus erythematosus. Rate ratios were considerably higher for some of these diseases than others: for example, for systemic lupus erythematosus the rate ratios were 3.61 (2.36 to 5.31) in the ORLS1 population, 4.60 (3.19 to 6.43) in ORLS2 and 3.71 (3.43 to 4.02) in the England dataset. CONCLUSIONS: People admitted to hospital with immune-mediated diseases may be at an increased risk of subsequent VTE. Our findings need independent confirmation or refutation; but, if confirmed, there may be a role for thromboprophylaxis in some patients with these diseases.
21189317 Glia-induced reversible disruption of blood-brain barrier integrity and neuropathological 2011 Jan The blood-brain barrier (BBB) is the regulated interface that mediates selective transcellular transport of nutrients and essential components from the blood into the brain parenchyma. Many neurodegenerative diseases including stroke, multiple sclerosis, rheumatoid arthritis, and AIDS dementia exhibit loss of BBB integrity. Despite the increasing body of evidence for the involvement of glia in maintaining the BBB, few studies have addressed glial/endothelial/extracellular matrix interactions. A chemically induced astrocyte lesion provides a noninvasive model to study reversible BBB dysfunction in vivo. Blood-brain barrier integrity was assessed with fluorescent dextran tracers (3-70 kDa) and magnetic resonance imaging, in parallel with confocal and electron microscopy imaging of the neurovascular unit. These studies demonstrated modified tight-junction protein expression with loss of vascular integrity. We propose that adherens junction proteins and extracellular matrix remodeling provide a temporary size-selective barrier, whereas astrocyte and microglia activation direct tight-junction proteins to paracellular domains and restore BBB integrity. Morphological comparisons were made with the area postrema, a circumventricular organ with a naturally porous BBB. Further studies into cellular mechanisms of glial/endothelial/extracellular matrix interactions may identify novel glial-based therapeutic targets and innovate therapies for modulating diseases in which gliosis and raised levels of pro-inflammatory mediators are central components.
21074639 Excess of autoimmune and chronic inflammatory disorders in patients with lymphoma compared 2011 Feb OBJECTIVE: We investigated the association between autoimmune and chronic inflammatory disorders and several cancer types including lymphomas. METHODS: All cancer patients diagnosed between 1995 and 2007, aged 15 to 90 years, and registered in the Eindhoven Cancer Registry were included in this study. Co-morbidity at diagnosis was recorded by qualified registry personnel who obtained the information from the clinical record. We determined the prevalence of rheumatoid arthritis (RA), chronic inflammatory bowel diseases, connective and vascular tissue diseases, ulcers of the stomach and duodenum, hepatitis, human immunodeficiency virus (HIV), and tuberculosis (TBC) among newly diagnosed patients with lymphoma and compared this with the prevalence among patients with all other cancers. RESULTS: The prevalence of most of these co-morbidities was higher in patients with lymphomas than those with other malignancies. RA was more often present in newly diagnosed patients with most lymphomas, ulcers of stomach and duodenum in patients with marginal zone lymphoma, hepatitis in case of diffuse large B-cell lymphoma, HIV with aggressive B-cell lymphoma, and TBC with mantle cell lymphoma. CONCLUSION: This study confirms the positive association between autoimmune and chronic inflammatory disorders and the various lymphoproliferative malignancies, suggesting either a shared etiology or pathogenesis or a direct causal relation. This is a fairly new method to study aetiological questions about cancers in a population-based cancer registry.
20490591 Anti-ribonucleoproteins autoantibodies in patients with systemic autoimmune diseases. Rela 2011 Feb A common feature between patients with a certain group of systemic autoimmune pathologies (SAPs) with rheumatic component, such as lupus erythematosus (LE) in all its forms, is the presence of cutaneous photosensitivity (CP) as well as the existence of autoantibodies (Aabs). These Aabs have also high incidence in other SAPs that do not present CP, like primary Sjögren's syndrome and rheumatoid arthritis. Cutaneous photosensitivity is a condition that consists of an exacerbated skin reaction to solar radiations; its incidence can reach 90% in systemic LE. The mechanisms involved in the development of CP have been extensively studied focusing on different approaches; however, the exact mechanism has not been fully elucidated yet. There are many theories that relate specifically the presence of circulating anti-Ro/SS-A Aabs with the CP phenomenon, though there are several studies which are in disagreement. In this study, we evaluated the Aabs profile (anti-Ro/SS-A 52 kDa, anti-Ro/SS-A 60 kDa, anti-La/SS-B, anti-Sm and ANAs) as well as their titer or reactivity, in a local cohort of 169 patients with SAPs. We related those Aabs profiles and titers with the presence or absence of CP, and we found that there was no significant association between the presence of anti-Ro/SS-A Aabs and the occurrence of CP. On the other hand, a statistically significant positive association was found between CP and high reactivity anti-Sm Aabs, though this fact could be biased by the incidence of both events in SLE patients. To sum up, in the particular population studied, there is no direct relationship between anti-Ro/SS-A Aabs and CP, which is in agreement with some authors and in disagreement with many others, contributing to the endless discussion of this issue.
22410002 A non-peptide receptor inhibitor with selectivity for one of the neutrophil formyl peptide 2012 Jun 15 The neutrophil formyl peptide receptors (FPR1 and FPR2) are members of the G-protein coupled receptor family. The signals generated by occupied FPRs are both pro-inflammatory and anti-inflammatory. Accordingly, these receptors have become a therapeutic target for the development of novel drugs that may be used to reduce injuries in inflammatory diseases including asthma, rheumatoid arthritis, Alzheimer's disease and cardiovascular diseases. To support the basis for a future pharmacological characterization, we have identified a small molecular non-peptide inhibitor with selectivity for FPR1. We used the FPR1 and FPR2 specific ligands fMLF and WKYMVM, respectively, and an earlier described ratio technique, to determine inhibitory activity combined with selectivity. We show that the compound 3,5-dichloro-N-(2-chloro-5-methyl-phenyl)-2-hydroxy-benzamide (BVT173187) fulfills the criteria for an FPR1 inhibitor selective for FPR1 over FPR2, and it inhibits the same functional repertoire in neutrophils as earlier described peptide antagonists. Accordingly, the new inhibitor reduced neutrophil activation with FPR1 agonists, leading to mobilization of adhesion molecules (CR3) and the generation of superoxide anion from the neutrophil NADPH-oxidase. The effects of a number of structural analogs were determined but these were either without activity or less active/specific than BVT173187. The potency of the new inhibitor for reduction of FPR1 activity was the same as that of the earlier described FPR1 antagonist cyclosporine H, but signaling through the C5aR and CXCR (recognizing IL8) was also affected by BVT173187.
23441388 Risk factors affecting the incidence of infection after orthopaedic surgery: the role of c 2012 Dec The incidence of surgical site infection and urinary tract infection following orthopaedic procedures has diminished in recent years due to modern antimicrobial prophylaxis. We conducted a case-control study (100 cases, 100 controls) in order to evaluate the risk factors associated with infection after orthopaedic procedures. The following risk factors were defined: gender, age, comorbidities [rheumatoid arthritis, diabetes mellitus, obesity (> 30 kg/m2), peripheral vessel disease], pre- and post-operative glucose levels, pre-operative and post-operative length of stay (days), duration (days) of urinary catheterization, type of parenteral antibiotic prophylaxis (cefotaxime or vancomycin), time of surgery (elective or scheduled), American Society of Anesthesiologists (ASA) Score (0-3), type of surgery (fracture osteosynthesis, joint replacement, spinal surgery, other), and the type of anesthesia administered (general, epidural, spinal). Urinary tract infection was the most frequent post-surgical infection (71 out of 100 cases) followed by surgical site infection (15 out of 100 cases). Using the multivariable logistic regression model, we found out that only the type of chemoprophylaxis was statistically significant risk factor (p < 0.001) associated with post-surgical infection. More specifically, the use of vancomycin instead of cephalosporin is associated with a lower risk of infection.
23275336 Inhibitor of apoptosis proteins (IAPs) and their antagonists regulate spontaneous and tumo 2013 Feb 15 Inhibitor of apoptosis proteins (IAPs) play a major role in determining whether cells undergo apoptosis in response to TNF as well as other stimuli. However, TNF is also highly proinflammatory through its ability to trigger the secretion of multiple inflammatory cytokines and chemokines, which is arguably the most important role of TNF in vivo. Indeed, deregulated production of TNF-induced cytokines is a major driver of inflammation in several autoimmune conditions such as rheumatoid arthritis. Here, we show that IAPs are required for the production of multiple TNF-induced proinflammatory mediators. Ablation or antagonism of IAPs potently suppressed TNF- or RIPK1-induced proinflammatory cytokine and chemokine production. Surprisingly, IAP antagonism also led to spontaneous production of chemokines, particularly RANTES, in vitro and in vivo. Thus, IAPs play a major role in influencing the production of multiple inflammatory mediators, arguing that these proteins are important regulators of inflammation in addition to apoptosis. Furthermore, small molecule IAP antagonists can modulate spontaneous as well as TNF-induced inflammatory responses, which may have implications for use of these agents in therapeutic settings.
23237994 Therapeutic immunomodulation in systemic vasculitis: taking stock. 2013 Jul Current data on therapeutic immunomodulation used to treat systemic vasculitides are reviewed in this paper, which also discusses ongoing and future developments in the field. In vasculitides associated with anti-neutrophil cytoplasmic antibodies, rituximab is a validated induction treatment that can serve as an alternative to cyclophosphamide and must be followed by maintenance treatment. In addition, the usefulness of rituximab as maintenance treatment was established recently. Immunoglobulins can be helpful adjuncts, most notably in patients with severe immunodepression. Plasmapheresis is indicated in patients with severe renal failure and may have a role in the treatment of alveolar hemorrhage syndromes. Mepolizumab has produced encouraging preliminary results in eosinophilic granulomatosis with polyangiitis (Churg-Strauss). Rituximab can be used in cryoglobulinemic vasculitis associated with hepatitis C virus infection when antiviral therapy fails or the disease is severe. Very low doses of interleukin-2 may be helpful in refractory forms. Rituximab is also an option in essential mixed cryoglobulinemia with uncontrolled vasculitis despite glucocorticoid and/or immunosuppressive treatment. In polyarteritis nodosa associated with the hepatitis B virus, a combination of short-course glucocorticoids, plasmapheresis, and antiviral therapy produces excellent outcomes. Intravenous immunoglobulins are used to treat Kawasaki disease, in which they diminish the incidence of coronary artery aneurysms. Several prospective controlled trials are currently assessing tocilizumab in giant-cell arteritis. Rituximab has useful effects in systemic vasculitis associated with rheumatoid arthritis. In Goodpasture's syndrome, plasmapheresis is indicated to clear the antibodies to glomerular membrane antigen, which can induce glomerulonephritis.
23233648 Large granular lymphocytic leukemia: molecular pathogenesis, clinical manifestations, and 2012 Large granular lymphocyte (LGL) leukemia represents a spectrum of rare lymphoproliferative diseases defined by clonal amplification of either CD3(+) cytotoxic T-lymphocytes or CD3(-) natural killer cells. This chapter focuses on the T-cell form of LGL leukemia. Clinical features include neutropenia, anemia, and rheumatoid arthritis. LGL leukemia is thought to arise from chronic antigenic stimulation, with the long-term survival of LGL being promoted by constitutive activation of multiple survival signaling pathways, such as the JAK/STAT3, sphingolipid, and Ras/MEK/ERK pathways. Therefore, these lead to global deregulation of apoptosis and resistance to normal pathways of activation-induced cell death. The majority of LGL leukemia patients eventually need treatment. Treatment of leukemic LGL is based on immunosuppressive therapy, primarily using low doses of methotrexate or cyclophosphamide. However, no standard therapy has been established because of the lack of large, prospective trials. In addition, because some patients are refractory to currently available treatments and none of these therapeutic modalities can cure LGL leukemia, new therapeutic options are needed. Understanding the current state of the pathogenesis of LGL leukemia may provide insights into novel therapeutic options.
23204561 Urethral caruncle: a lesion related to IgG4-associated sclerosing disease? 2013 Jul AIMS: Urethral caruncle is a benign, polypoid urethral mass that occurs almost exclusively in postmenopausal women. Despite that these lesions are routinely managed with topical medications or excision, their pathogenesis is not well understood. We investigated the possibilities of autoimmune, viral and inflammatory myofibroblastic proliferations as possible aetiologies. METHODS: In 38 patients with urethral caruncle, we utilised immunohistochemistry for immunoglobulin G (IgG) and IgG4 to assess for a potential autoimmune aetiology. Immunohistochemistry was performed in nine patients for Epstein-Barr virus, BK virus, human herpesvirus 8, human papillomavirus, adenovirus and anaplastic lymphoma kinase. RESULTS: Four patients (11%) showed infiltrates of ≥50 IgG4-positive plasma cells per high power field, of which all showed an IgG4 to IgG ratio greater than 40%. A statistically significant difference (p<0.01) was detected in the mean number of IgG4-positive cells (14.73 per high power field) compared with control benign urethral specimens (mean, 1.19). One patient with increased counts below this threshold had rheumatoid arthritis; none had documented autoimmune pancreatitis or other known manifestations of systemic IgG4-related sclerosing disease. All lesions showed negative reactions for the viral and inflammatory myofibroblastic markers. CONCLUSIONS: Urethral caruncle is a benign inflammatory and fibrous polypoid urethral mass of unclear aetiology. It appears unrelated to viral infection and lacks the abnormal expression of anaplastic lymphoma kinase protein, as seen in inflammatory myofibroblastic tumours. Increased numbers of IgG4-positive plasma cells in a subset of lesions raise the possibility that some cases may be related to the autoimmune phenomena of IgG4-associated disease.