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ID PMID Title PublicationDate abstract
19190822 Uncarboxylated matrix Gla protein (ucMGP) is associated with coronary artery calcification 2009 Feb Matrix gamma-carboxyglutamate (Gla) protein (MGP) is a potent local inhibitor of cardiovascular calcification and accumulates at areas of calcification in its uncarboxylated form (ucMGP). We previously found significantly lower circulating ucMGP levels in patients with a high vascular calcification burden. Here we report on the potential of circulating ucMGP to serve as a biomarker for vascular calcification in haemodialysis (HD) patients. Circulating ucMGP levels were measured with an ELISA-based assay in 40 HD patients who underwent multi-slice computed tomography (MSCT) scanning to quantify the extent of coronary artery calcification (CAC). The mean ucMGP level in HD patients (193 +/- 65 nM) was significantly lower as compared to apparently healthy subjects of the same age (441 +/- 97 nM; p < 0.001) and patients with rheumatoid arthritis (RA) without CAC (560 +/- 140 nM; p < 0.001). Additionally, ucMGP levels correlated inversely with CAC scores (r = -0.41; p = 0.009), and this correlation persisted after adjustment for age, dialysis vintage and high-sensitivity C-reactive protein (hs-CRP). Since circulating ucMGP levels are significantly and inversely correlated with the extent of CAC in HD patients, ucMGP may become a tool for identifying HD patients with a high probability of cardiovascular calcification.
19184540 The emerging field of osteoimmunology. 2009 Dec Recent studies have elucidated unanticipated connections between the immune and skeletal systems, and this relationship has led to the development of a new field known as osteoimmunology. The goal of research in this field is to: (1) further understand how the bone microenvironment influences immune cell ontogeny and subsequent effector functions, and (2) translate basic science findings in bone biology to clinical applications for autoimmune diseases that target the skeleton such as rheumatoid arthritis (RA). In this review, we will examine the recent findings of the interplay between the immune and skeletal systems. This discussion will focus on the cells and signaling pathways in osteoimmune interactions and how innate and adaptive immune effector cells as well as cytokines and chemokines play a role in the maintenance and dysregulation of skeletal-immune homeostasis. We will also discuss how immunomodulatory biologic drugs, which specifically target these cells and effector molecules, have transformed the treatment of autoimmune mediated inflammatory diseases (IMIDs) and metabolic bone diseases such as osteoporosis.
20471860 Inhibition of bleomycin-induced pulmonary fibrosis through pre-treatment with collagen typ 2010 Aug BACKGROUND: Tolerance to collagen structures has been shown to inhibit the progression of autoimmune scleroderma and rheumatoid arthritis. More recently, tolerance induction to collagen type V (colV) in experimental models of lung transplantation was shown to ameliorate the complex pathology known as "chronic rejection." The link between colV autoimmunity and progressive graft dysfunction and subsequent development of bronchiolitis obliterans syndrome (BOS) has been established in human lung transplant recipients. We hypothesized that intravenous injection of colV inhibits development of lung fibrosis in a bleomycin-induced lung injury mouse model. METHODS: Experimental animals were injected intravenously with saline or colV 10 days before intratracheal instillation of bleomycin. Pulmonary inflammation was monitored and quantified for the presence of cells in the bronchoalveolar lavage (BAL) fluid by flow cytometry and histology of lung tissue. RESULTS: ColV-pre-treated animals showed a significant reduction in lung inflammation compared with non-treated animals, according to histology and morphometry. The number of inflammatory cells in the BAL fluid was significantly reduced and associated with a lower proportion of gammadelta T cells and CD4(+) T cells in the colV-pre-treated group. Matrix metalloproteinase-2 and -9 (MMP-2 and -9; also known as gelatinase A and gelatinase B, respectively) levels in the BAL fluid were significantly reduced in colV-pre-treated mice compared with the non-treated mice. In addition, intravenous injection of colV was associated with a significant reduction in the relative expression of interleukin (IL)-6, IL-17 and IL-22 in cells present in BAL fluid at 7 and 14 days after bleomycin instillation. CONCLUSIONS: Pre-treatment by intravenous injection of colV inhibits bleomycin-induced pulmonary fibrosis by inhibiting IL-6 and IL-17 production. Fibrosis treatment in this context therefore should target induction of colV tolerance and Th17 development.
20231208 Interstitial lung disease associated with anti-PM/Scl or anti-aminoacyl-tRNA synthetase au 2010 May OBJECTIVE: To compare anti-PM/Scl autoantibody-associated interstitial lung disease (ILD) with anti-aminoacyl-tRNA synthetases (anti-ARS) autoantibody-associated ILD. METHODS: We retrospectively studied 21 patients with ILD from a department of respiratory medicine, including 9 with anti-PM/Scl autoantibodies (6 women, median age 55 yrs, followup 5.5 yrs) and 12 with anti-ARS autoantibodies (6 women, median age 59 yrs, followup 2.3 yrs). RESULTS: Pulmonary manifestations in patients with anti-PM/Scl autoantibody-associated ILD usually followed the extrapulmonary manifestations of the connective tissue disease (CTD) (7/9 cases). The predominant imaging features on initial high resolution computed tomography were ground-glass attenuation and reticular opacities, and mainly suggested nonspecific interstitial pneumonia in both groups. CTD was classified as dermatomyositis (DM; 2), undifferentiated CTD (2), cutaneous limited systemic sclerosis (2), rheumatoid arthritis (RA; 1), and overlap syndrome (1) in the anti-PM/Scl group; and polymyositis (4), undifferentiated CTD (5), DM (1), amyopathic DM (1), and RA (1) in the anti-ARS group. Frequencies of arthralgia, Raynaud phenomenon, cutaneous rash, and mechanic's hands were comparable in both groups. Myalgia or muscle weakness was present in 0/9 PM/Scl and 5/12 ARS patients (p < 0.05). More than 1 autoantibody was present in 11 patients. ILD worsened despite treatment in 4 patients with anti-PM/Scl autoantibodies and 2 with anti-ARS autoantibodies, and included 1 death. CONCLUSION: Anti-PM/Scl and anti-ARS antibodies are associated with similar clinical manifestations, with the exception only of more overt myositis in the latter, therefore challenging the clinical specificity of the antisynthetase syndrome.
20230970 Implant location and radiotherapy are the only factors linked to 2-year implant failure. 2010 Mar SUBJECTS: The subjects in this retrospective case series were derived from a review of 700 patient files within the implant practice of the Department of Periodontology, University Hospital, Catholic University of Leuven. Inclusion criteria were met by 412 patients (240 females, 172 males) receiving a total of 1514 Nobel Biocare dental implants. These patients were included based on data availability for the time period 2 years after abutment surgery (considered to represent late implant failure). KEY EXPOSURE/STUDY FACTOR: Given the concern of the authors to assess the probability of late implant failure among clinic patients with certain local and systemic factors, the potential factors were multiple. The local factors included the following: implant length and diameter, bone quality and quantity, insertion site, type of edentulism, antibiotic use perioperatively, dehiscence and/or perforation of the site during surgery, and stability at insertion (measured by Periotest values). The related health and behavioral factors included the following: medications, smoking (<10 cigarettes/day, 10-20 cigarettes/ day, >20 cigarettes/day), hypertension, ischemic cardiac problems, coagulation anomalies, gastric ulcers, thyroid disorders, hypercholesterolemia,rheumatoid arthritis, asthma, diabetes (types 1 and 2), Crohn's disease, and chemotherapy. MAIN OUTCOME MEASURE: The primary outcome was described as "late implant failure." The current study, which follows a similar study on early implant failure, aims to identify negative influences on maintenance of integration. The authors used the clinical experience related to the 412 patients with 1514 implants to identify whether the observed failure rates were influenced by local and systemic factors. Failure was defined as "late" when occurring between abutment connection surgery and 2 years after this date. Patients/implants that were not available for this interval of time were not included. However, even when records were available, not all patient records provided all data sought. MAIN RESULTS: Regarding local factors, the authors reported that implant diameter and location were relevant to late implant loss, whereas implant length was not (P value = .01, = .34, respectively; univariate generalized estimating equation [GEE] logistic regression). Regarding implant diameter, significantly more loss was noted for 5.00-mm implants when compared with the 4.00-mm or 4.75-mm implants. Failure related to location revealed that the maxilla compared with the mandible, posterior jaws compared with anterior jaws, and the posterior maxilla compared with all other oral locations were associated with more late failures (Table 1). Assessment of systemic factors revealed radiotherapy to be related to more late implant loss (P = .003). Neither systemic disease nor smoking exposure was associated with late failure. CONCLUSIONS: The authors concluded that late implant failure was influenced by the local factor "implant location" and the systemic factor "radiotherapy." Neither smoking nor systemic health factors were found to adversely influence implant integration from abutment connection through 2 years' performance.
20230629 Two additive mechanisms impair the differentiation of 'substrate-selective' p38 inhibitors 2010 Mar 15 BACKGROUND: The success of anti-TNF biologics for the treatment of rheumatoid arthritis has highlighted the importance of understanding the intracellular pathways that regulate TNF production in the quest for an orally-available small molecule inhibitor. p38 is known to strongly regulate TNF production via MK2. The failure of several p38 inhibitors in the clinic suggests the importance of other downstream pathways in normal cell function. Recent work has described a 'substrate-selective' p38 inhibitor that is able to preferentially block the activity of p38 against one substrate (MK2) versus another (ATF2). Using a combined experimental and computational approach, we have examined this mechanism in greater detail for two p38 substrates, MK2 and ATF2. RESULTS: We found that in a dual (MK2 and ATF2) substrate assay, MK2-p38 interaction reduced the activity of p38 against ATF2. We further constructed a detailed kinetic mechanistic model of p38 phosphorylation in the presence of multiple substrates and successfully predicted the performance of classical and so-called 'substrate-selective' p38 inhibitors in the dual substrate assay. Importantly, it was found that excess MK2 results in a stoichiometric effect in which the formation of p38-MK2-inhibitor complex prevents the phosphorylation of ATF2, despite the preference of the compound for the p38-MK2 complex over the p38-ATF2 complex. MK2 and p38 protein expression levels were quantified in U937, Thp-1 and PBMCs and found that [MK2] > [p38]. CONCLUSION: Our integrated mechanistic modeling and experimental validation provides an example of how systems biology approaches can be applied to drug discovery and provide a basis for decision-making with limited chemical matter. We find that, given our current understanding, it is unlikely that 'substrate-selective' inhibitors of p38 will work as originally intended when placed in the context of more complex cellular environments, largely due to a stoichiometric excess of MK2 relative to p38.
19666505 Circulating CD21low B cells in common variable immunodeficiency resemble tissue homing, in 2009 Aug 11 The homeostasis of circulating B cell subsets in the peripheral blood of healthy adults is well regulated, but in disease it can be severely disturbed. Thus, a subgroup of patients with common variable immunodeficiency (CVID) presents with an extraordinary expansion of an unusual B cell population characterized by the low expression of CD21. CD21(low) B cells are polyclonal, unmutated IgM(+)IgD(+) B cells but carry a highly distinct gene expression profile which differs from conventional naïve B cells. Interestingly, while clearly not representing a memory population, they do share several features with the recently defined memory-like tissue, Fc receptor-like 4 positive B cell population in the tonsils of healthy donors. CD21(low) B cells show signs of previous activation and proliferation in vivo, while exhibiting defective calcium signaling and poor proliferation in response to B cell receptor stimulation. CD21(low) B cells express decreased amounts of homeostatic but increased levels of inflammatory chemokine receptors. This might explain their preferential homing to peripheral tissues like the bronchoalveolar space of CVID or the synovium of rheumatoid arthritis patients. Therefore, as a result of the close resemblance to the gene expression profile, phenotype, function and preferential tissue homing of murine B1 B cells, we suggest that CD21(low) B cells represent a human innate-like B cell population.
19640854 Serious infections in patients with ankylosing spondylitis with and without TNF blockers: 2010 Oct BACKGROUND: Tumour necrosis factor (TNF) blockers are known to increase the risk of serious infections in rheumatoid arthritis. Despite wide use of TNF blockers in ankylosing spondylitis (AS), the infection risk has never been evaluated in this disease. OBJECTIVES: To assess serious infections in patients with AS not exposed and exposed to TNF blockers. METHODS: A systematic literature review up to May 2008 using PubMed, EMBASE and Cochrane Library was performed. All randomised controlled trials (RCTs) published between 1995 and 2008 monitoring serious infections, treated with non-steroidal anti-inflammatory drugs (NSAIDs) or TNF blockers, were included. Infection risks were calculated by naive pooling and for 100 patient-years (pyrs) of exposure. To assess the serious infection risk with TNF blockers, a meta-analysis of RCTs was performed using Mantel-Haenszel's method with several sensitivity analyses. RESULTS: Fourteen RCTs were included (3345 patients). With placebo or NSAIDs (N=2202), two serious infections were observed (0.09%, range 0.01% to 0.3%)-that is, 0.4/100 pyrs. In TNF blocker trials, two serious infections were observed with placebo (2/500, 0.4% (0.0% to 1.4%), ie, 1.0/100 pyrs) versus 14 serious infections with TNF blockers (14/996, 0.7% (0.3% to 1.4%), ie, 1.9/100 pyrs). Meta-analysis of the RCTs showed that the increase in serious infections with TNF blockers compared with placebo was not significant: risk difference=0.4% (-0.8% [corrected] to 1.6%). CONCLUSIONS: The absolute risk of serious infections in patients with AS not exposed to TNF blockers is low. The absolute risk of serious infections in patients receiving TNF blockers is higher, but the difference was found to be not significant, possibly through lack of power. Continued monitoring is necessary.
19374160 Clinical competence for autoimmune and non-autoimmune rheumatic disorders in primary care. 2009 Jan OBJECTIVE: To evaluate the competence of the primary care physicians for the evaluation of rheumatic disorders. PARTICIPANTS AND METHODS: In a cross-sectional survey we included primary care physicians working at the official Mexican Social Security Institute that provides nation-wide health-care for salaried workers. Four hospitals from 23 potentially eligible primary-care hospitals in Guadalajara, Jalisco, Mexico, were randomly selected. From these hospitals the physicians who agree to participate were asked to answer a questionnaire for clinical competence. Using a Delphi modified approach; this questionnaire was elaborated by a group of rheumatologists and researchers working in continuous medical education. A Kuder-Richardson reliability index was computed in 0.94. The diseases included in the questionnaire were: (1) rheumatoid arthritis, (2) Sjogren syndrome, 3) gout, 4) osteoarthritis and 5) systemic lupus erythematosus and questions regarding to these were made using the technique of "representative patients". Domains included in the questionnaire were: assessment of risk factors, strategies for diagnosis, and treatment. According to the scores obtained in the questionnaire the ranges for clinical competence were: very high level 93-110 points, high level 75-92, moderate 57-74, low 39-56, very low 21-38 and <20 points was considered obtained by chance. RESULTS: One-hundred and four primary care physicians were interviewed. From the total, 60 (58%) physicians had the speciality of family physician. Only 11% (95% CI 5-17) of the interviewed had a high level of competence according to the instrument. Moderate competence was achieved by 20% (95% CI 13-27), whereas suboptimal levels had 51%: being low 31% (95% CI 22-40), very low 20% (95% CI 13-27). An additional 18% had scores obtained by chance (95% CI 11-25). There was no statistical difference in the scores between physicians with or without the specialty in family medicine. CONCLUSIONS: These results pointed-out a sub-optimal competence in a significant proportion of the primary care-physicians attending rheumatic disorders. Higher efforts need to be made to increase the levels of competence and improve the effectiveness of continuous medical education for these physicians.
19113932 A simple risk score for the assessment of absolute fracture risk in general practice based 2009 May The aim of this prospective study was to develop a risk score, based on putative risk factors in current guidelines, which can be used to identify women at high risk of fractures in general practice. The study sample included 4157 women >/=60 yr of age (mean +/- SD: 74.1 +/- 9.1 yr), with a median follow-up of 8.9 yr of the Rotterdam Study (ERGO), and 762 women >/=65 yr of age (mean +/- SD: 76.0 +/- 6.7.yr), with a median follow-up of 6.0 yr of the Longitudinal Aging Study Amsterdam (LASA). Potential risk factors were those proposed in risk scores of three recent guidelines on osteoporosis: age, family history of fractures, prior fracture, low body weight/body mass index (BMI), serious immobility, rheumatoid arthritis, current smoking, alcohol consumption >2 units daily, prevalent vertebral fracture, and systemic corticosteroid use. Five-year absolute risk of hip fracture was 3.9% in the Rotterdam Study and 3.1% in LASA, and 10-yr absolute risk of hip fracture was 8.4% in the Rotterdam Study. Using Cox regression analysis, age (70-79 and 80+ versus <60-69) and four other risk factors were included in the risk profiles of hip fractures and fragility fractures: any prior fracture after age 50, body weight <64 kg, use of a walking aid as a proxy measure of serious immobility, and current smoking. Estimated 10-yr absolute risk of hip fracture ranged from 1.4% in women, age 60-69 years, without any of these predictors to 29% in women, >/=80 yr of age, having two or more positive risk factors. A simple risk score can satisfactorily identify older women at high risk of osteoporotic fractures in general practice. Future studies are needed to validate this score.
18923992 Induction and exacerbation of psoriasis with TNF-blockade therapy: a review and analysis o 2009 BACKGROUND: There are reports of rare adverse effects of tumor necrosis factor (TNF) inhibitors, including infections, malignancies, and induction of autoimmune conditions. Intriguing, are cases of induction or exacerbation of psoriasis in conjunction with TNF inhibitor therapy, given that they are approved for treatment of the same condition. OBJECTIVE: Published cases of psoriasis occurring during anti-TNF therapy were analyzed, including overviews of proposed etiologies and treatment recommendations. METHODS: A literature search using Ovid MEDLINE and PubMed was performed for articles published between January 1990 and September 2007 to collect reported cases of psoriasis in patients receiving therapy with TNF blocking agents. RESULTS: A total of 127 cases were identified: 70 in patients on infliximab (55.1%), 35 with etanercept (27.6%), and 22 with adalimumab (17.3%). Females comprised 58% of cases; mean age of reported patients was 45.8 years, and the time from initiation of treatment to onset of lesions averaged 10.5 months. These patients suffered from a number of primary conditions, with rheumatoid arthritis, ankylosing spondylitis, and Crohn's disease accounting for the vast majority. Palmoplantar pustular psoriasis was observed in 40.5% of the cases, with plaque-type psoriasis in 33.1%, and other types comprising the remainder. Topical corticosteroids were the most commonly employed treatment modality but led to resolution in only 26.8% of cases in which they were employed solely. Switching to a different anti-TNF agent led to resolution in 15.4% of cases. Cessation of anti-TNF therapy with systemic therapy led to resolution in 64.3% of cases. CONCLUSION: More information and cases are needed. Biopsies of TNF-blockade-induced lesions may reveal what cytokines and cell types drive the development of these lesions. Additionally, there is a need to develop an algorithm to treat this paradoxical side effect of therapy with TNF-blockers.
21135874 Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase. 2011 Jan The IκB kinase (IKK) complex plays a well-documented role in innate and adaptive immunity. This function has been widely attributed to its role as the central activator of the NF-κB family of transcription factors. However, another important consequence of IKK activation is the regulation of TPL-2, a MEK kinase that is required for activation of ERK-1/2 MAP kinases in myeloid cells following Toll-like receptor and TNF receptor stimulation. In unstimulated cells, TPL-2 is stoichiometrically complexed with the NF-κB inhibitory protein NF-κB1 p105, which blocks TPL-2 access to its substrate MEK, and the ubiquitin-binding protein ABIN-2 (A20-binding inhibitor of NF-κB 2), both of which are required to maintain TPL-2 protein stability. Following agonist stimulation, the IKK complex phosphorylates p105, triggering its K48-linked ubiquitination and degradation by the proteasome. This releases TPL-2 from p105-mediated inhibition, facilitating activation of MEK, in addition to modulating NF-κB activation by liberating associated Rel subunits for translocation into the nucleus. IKK-induced proteolysis of p105, therefore, can directly regulate both NF-κB and ERK MAP kinase activation via NF-κB1 p105. TPL-2 is critical for production of the proinflammatory cytokine TNF during inflammatory responses. Consequently, there has been considerable interest in the pharmaceutical industry to develop selective TPL-2 inhibitors as drugs for the treatment of TNF-dependent inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. This review summarizes our current understanding of the regulation of TPL-2 signaling function, and also the complex positive and negative roles of TPL-2 in immune and inflammatory responses.
21063098 Periplocin inhibits growth of lung cancer in vitro and in vivo by blocking AKT/ERK signali 2010 Periplocin is one of cardenolides isolated from cortex periplocae which is used for treatment of rheumatoid arthritis and reinforcement of bones and tendons in traditional medicine. Here, we investigated the anti-tumor activity of periplocin against lung cancer cells bothin vitro and in vivo, and explored its anti-cancer mechanism. Periplocin inhibited the growth of lung cancer cells and induced their apoptosis in time- and dose-dependent manners by cell cycle arrest in G0/G1 phase. Periplocin exhibited anti-tumor activity both in human (A549) and mouse (LL/2) lung cancer xenograft models. Immunohistochemical analysis revealed that intratumoral angiogenesis was significantly suppressed. Furthermore, anti-cancer activity mediated by periplocin was associated with decreased level of phosphorylated AKT and ERK both in vitro and in vivo, which were important for cell growth and survival. Moreover, periplocin induced apoptosis by downregulating Bcl-2 and upregulating Bax, leading to activation of caspase-3 and caspase-9. These findings suggested that periplocin could inhibit the growth of lung cancer both in vitro and in vivo, which could be attributed to the inhibition of proliferation and the induction of apoptosis signaling pathway, such as AKT and ERK. These observations provide further evidence on the anti-tumor effect of periplocin, and it may be of importance to further explore its potential role as a therapeutic agent for cancer.
20943041 Divergent and synergistic regulation of matrix metalloprotease production by cytokines in 2010 Jul The chemotactic effects of chemokines on cells has long been known, but it is now clear that chemokines also have much broader activities and are also involved in a number of disease pathologies, such as rheumatoid arthritis, cancer metastasis and other inflammatory processes. This study investigates the effects of four C-C chemokines, CCL2, CCL3, CCL4 and CCL5 either alone or in the presence of two regulatory cytokines TNF-alpha and TGF-beta and their effect on secretion of two matrix metalloproteases MMP, MMP-2 and MMP-9, and the expression of one membrane bound MMP, MMP-14, by a monocytic human cell line, MonoMac6. All four C-C chemokines were shown to be chemotactic, but only CCL2 and CCL4 had any significant stimulatory effect on MMP-9 and MMP-2, respectively. Both TNF-alpha and TGF-beta were found to divergently enhance MMP-9 and MMP-2 secretion respectively, with stimulation indexes of two and five respectively. Simultaneous treatment with TNF-alpha and chemokine resulted in up to a fifteen-fold stimulation of MMP-9 secretion and treatment with TGF-beta and chemokine resulted in up to a fifteen-fold stimulation of MMP-2 secretion, while TNF-alpha in combination with CCL4 stimulated MMP-14 expression five-fold. Chemokine receptor expression was also investigated using a calcium-sensitive dye and FACS analysis. CCL2, CCL3, and CCL5 all resulted in a detectable enhancement of cytoplasmic Ca2+concentration. CCL4 was unable to activate Ca2+ mobilization, despite the presence of CCR5, the receptor for CCL4. There appeared to be no correlation between MMP production and chemotaxis. The strong synergy between chemokines and cytokines and the enhanced production of MMP may signify the differential regulatory mechanisms of the two cytokines and chemokines in disease pathology.
20938025 Incidence of progressive multifocal leukoencephalopathy in patients without HIV. 2010 Oct 12 OBJECTIVE: To estimate the incidence rate (IR) of progressive multifocal leukoencephalopathy (PML) in patients without HIV. METHODS: Within a large US health insurer database between January 2000 and June 2008, we conducted a retrospective observational study. We identified people with autoimmune diseases, chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), or history of bone marrow or solid organ transplantation, and a general population cohort. We developed a PML case-finding algorithm and validated PML diagnoses in medical charts. RESULTS: There were 138,469 patients with autoimmune diseases, 25,706 with NHL or CLL, and 8,778 with transplants. Among 699 people who met screening criteria for potential PML, 89 had a claim diagnosis of PML (International Classification of Diseases-9 046.3). Medical records were sought for 24 patients without HIV, and 6 had confirmed PML upon review of medical records. The PML IR was 2.4 (95% confidence interval [CI] 0.06-13.18) in the systemic lupus erythematosus cohort and 10.8 (95% CI 0.27-60.39) in the autoimmune vasculitis cohort per 100,000 person-years. In the NHL and CLL cohorts, the IR was 8.3 (95% CI 1.71-24.24) and 11.1 (0.28-61.74) per 100,000 person-years. The IR among patients with bone marrow transplantation was 35.4 per 100,000 person-years (95% CI 0.90-197.29). There were no cases of PML among patients with rheumatoid arthritis (95% CI 0.0-2.24), multiple sclerosis (95% CI 0.0-5.24), Sjögren disease (95% CI 0.0-21.84), or solid organ transplantation (95% CI 0.0-26.81). CONCLUSIONS: In this large population-based investigation of PML with thorough case finding and a known source population, the IR of medical record-confirmed PML was rare in non-HIV patient cohorts.
20726688 Biological agents in kidney transplantation: belatacept is entering the field. 2010 Oct IMPORTANCE OF THE FIELD: Kidney transplantation is the best treatment for end-stage kidney-disease patients. However, despite major breakthroughs in the last decades, and the progresses made with immunosuppressants, the long-term results still need to be improved. This is related to the increased risk of cardiovascular mortality, de novo post-transplant malignancies, and chronic kidney disease within the allograft. The last is multifactorial and includes immunological and non-immunological factors. Amongst the last is the calcineurin inhibitor (CNI) (cyclosporine A (CsA) and tacrolimus)-related nephrotoxicity. Kidney-allograft function at 1-year post-transplantation is a good surrogate marker of long-term allograft survival. AREAS COVERED IN THIS REVIEW: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4)-Ig, a fusion protein, presents as abatacept, which conserves the natural structure of CTLA4, and belatacept, which has enhanced activity thanks to two amino-acid substitutions. Abatacept and belatacept block CD86-CD28 interaction, but belatacept blocks them more powerfully. Abatacept is already approved for the treatment of rheumatoid arthritis and is marketed as Orencia(®) (Bristol-Myers Squibb, Princeton, NJ, USA), whereas belatacept is not yet approved. Herein, we review the current data available on the use of belatacept in Phase II and III kidney-transplantation trials. Note, though, that data from belatacept Phase II liver transplantation trials are not yet available. WHAT THE READER WILL GAIN: The results show in de novo kidney transplant patients that as compared to CsA-treated patients, belatacept-treated patients showed: i) a significant better allograft function both at 1- and 2- year post-transplantation and ii) better cardiovascular and metabolic profiles. Regarding the safety data, Epstein-Barr virus (EBV) seronegative belatacept-treated patients experience more post-transplant lymphoproliferative disorders than the EBV seropositive belatacept-treated patients and the CsA-treated patients. TAKE HOME MESSAGE: CNIs are potent immunosuppressants but have some degree of nephrotoxicity. Therefore, it is important to have strong data showing that belatacept-based therapy is as efficient as CsA-based therapy, but displaying at both 1- and 2-year post-transplantation a better allograft function, which might translate in the long-term into longer allograft survival.
20412788 Alisol-B, a novel phyto-steroid, suppresses the RANKL-induced osteoclast formation and pre 2010 Aug 1 Osteoclasts, bone-resorbing multinucleated cells, are differentiated from hemopoietic progenitors of the monocyte/macrophage lineage. Bone resorption by osteoclasts is considered a potential therapeutic target to the treatment of erosive bone diseases, including osteoporosis, rheumatoid arthritis, and periodontitis. In the present study, we found that alisol-B, a phyto-steroid from Alisma orientale Juzepczuk, exhibited inhibitory effects on osteoclastogenesis both in vitro and in vivo. Although RT-PCR analysis showed that alisol-B did not affect the 1alpha,25(OH)(2)D(3)-induced expressions of RANKL, OPG and M-CSF mRNAs in osteoblasts, addition of alisol-B to co-cultures of mouse bone marrow cells and primary osteoblasts with 10(-8)M 1alpha,25(OH)(2)D(3) caused significant inhibition of osteoclastogenesis. We further examined the direct effects of alisol-B on osteoclast precursors. Alisol-B strongly inhibited RANKL-induced osteoclast formation when added during the early stage of cultures, suggesting that alisol-B acts on osteoclast precursors to inhibit RANKL/RANK signaling. Among the RANK signaling pathways, alisol-B inhibited the phosphorylation of JNK, which are upregulated in response to RANKL in bone marrow macrophages, alisol-B also inhibited RANKL-induced expression of NFATc1 and c-Fos, which are key transcription factors for osteoclastogenesis. In addition, alisol-B suppressed the pit-forming activity and disrupted the actin ring formation of mature osteoclasts. In a hypercalcemic mouse model induced by 2-methylene-19-nor-(20S)-1alpha,25(OH)(2)D(3) (2MD), an analog of 1alpha,25(OH)(2)D(3), administration of alisol-B significantly suppressed 2MD-induced hypercalcemia as resulting from the inhibition of osteoclastogenesis. Taken together, these findings suggest that alisol-B may be a potential novel therapeutic molecule for bone disorders by targeting the differentiation of osteoclasts as well as their functions.
20059602 Clinical heterogeneity and prognostic features of South Australian patients with anti-synt 2011 Sep AIM: To determine the clinical, serological and prognostic features of patients with autoantibodies against three aminoacyl-transfer RNA synthetases (ARS), namely Jo-1 (histidyl-tRNA synthetase), PL-7 (threonyl-tRNA synthetase) and PL-12 (alanyl-tRNA synthetase) in South Australia. METHODS: Patients with autoantibodies against ARS detected by line immunoassay (anti-Jo1, anti-PL7, anti-PL12) or enzyme-linked immunosorbent assay (anti-Jo1) were identified from existing laboratory databases for the period 1994-2009. Demographic, clinical and serological data were obtained by retrospective review of patients' medical records and laboratory databases. RESULTS: Forty-two patients with autoantibodies were identified (anti-Jo1 = 37, anti-PL7 = 4, anti-PL12 = 1). Females were more commonly affected than males (M : F = 12:30). Twenty-one patients had polymyositis (anti-Jo1 = 17, anti-PL7 = 4), seven dermatomyositis (anti-Jo1 = 6, anti-PL12 = 1), 10 overlap syndrome (anti-Jo1 = 10; lupus = 4, scleroderma = 3, Sjögren's syndrome = 2 and rheumatoid arthritis = 2) and four had interstitial lung disease (ILD) only (anti-Jo1 = 4). ILD was present in 69%, polyarthritis in 59% and positive anti-nuclear antibody (ANA) in 43% of patients. Concurrence of autoantibodies against Ro-52 with Jo-1 was seen in 12 patients. The mean follow-up period was 8.3 years (95% CI 5.8-10.8) with 12 deaths. Poor prognostic indicators were age of onset >60 years (P= 0.001), cancer (P= 0.002), negative ANA (P= 0.006) and negative autoantibodies to extractable nuclear antigens (P= 0.02). CONCLUSION: Patients with autoantibodies against ARS present with varied clinical features and occasionally with isolated lung involvement (amyopathic ILD). Older age of onset, malignancy and negative immunologic tests are predictors of poor prognosis. Concurrence of autoantibodies against Jo-1 and Ro-52 may reflect a coupling effect during generation of autoimmunity.
19881230 Effectiveness of aquatic exercise and balneotherapy: a summary of systematic reviews based 2010 BACKGROUND: The objective of this review was to summarize findings on aquatic exercise and balneotherapy and to assess the quality of systematic reviews based on randomized controlled trials. METHODS: Studies were eligible if they were systematic reviews based on randomized clinical trials (with or without a meta-analysis) that included at least 1 treatment group that received aquatic exercise or balneotherapy. We searched the following databases: Cochrane Database Systematic Review, MEDLINE, CINAHL, Web of Science, JDream II, and Ichushi-Web for articles published from the year 1990 to August 17, 2008. RESULTS: We found evidence that aquatic exercise had small but statistically significant effects on pain relief and related outcome measures of locomotor diseases (eg, arthritis, rheumatoid diseases, and low back pain). However, long-term effectiveness was unclear. Because evidence was lacking due to the poor methodological quality of balneotherapy studies, we were unable to make any conclusions on the effects of intervention. There were frequent flaws regarding the description of excluded RCTs and the assessment of publication bias in several trials. Two of the present authors independently assessed the quality of articles using the AMSTAR checklist. CONCLUSIONS: Aquatic exercise had a small but statistically significant short-term effect on locomotor diseases. However, the effectiveness of balneotherapy in curing disease or improving health remains unclear.
20408860 Polymerase chain reaction (PCR) detection of B cell clonality in Sjögren's syndrome patie 2010 Jul 1 Sjögren's syndrome (SS) is an autoimmune disease characterized by clonal B cell attack of the exocrine glands and dysregulated expression of B cell-activating factor (BAFF). Based upon the current data of increased rates of lymphoid malignancy, as non-Hodgkin's lymphoma (NHL) is associated with SS, we propose the detection of clonal rearrangements of immunoglobulin heavy chain (IgH) gene in those patients as a predictor of malignant clonal expansion. To test our proposal, we examined the IgH clonal rearrangements in SS patients (60) and healthy control subjects (42) having chronic non-specific sialadenitis, to determine the presence of clonal B cells in minor labial salivary glands (MSG) of SS patients. Clonal B cell expansion was assessed by two polymerase chain reaction (PCR) assays: (i) semi-nested PCR, against sequences encoding framework regions FR3, FR2 and FR1c of the variable chain IgH gene in B cells present in the MSG infiltrate; and (ii) the PCR-enzyme-linked immunosorbent assay (ELISA) technique, against the major and minor breakpoint regions of the Bcl-2 oncogene coupled with a variable segment of the IgH to assess the Bcl-2/JH translocation. When FR3, FR2 and FR1c primers were employed, we detected B cell monoclonality in 87% of the SS patients and 19% of the control subjects. The association between inflammation severity of the MSG pattern and the presence of B cell clonality was found to be statistically significant (P<0.01). We concluded that the presence of B cell clonality in MSG can be used as a index of an altered microenvironment favouring the development of lymphoma in SS patients.