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ID PMID Title PublicationDate abstract
25577153 Prevalence of osteoporotic vertebral fracture in Spanish women over age 45. 2015 Mar The aim of this work is to study the prevalence of osteoporotic vertebral fractures in Spanish women over 45 years of age, based on the selection of a nationwide sample. An observational, cross-sectional, multicenter study was conducted during 2006, in all of Spain's regions. The sample analyzed was of 5000 individuals, representative of the female population over age 45 in Spain. A questionnaire was used to determine which factors are most often associated with vertebral fractures. We also assessed whether the Prevalent Vertebral Fracture Index, proposed by Vogt, is useful in indicating a possible osteoporotic vertebral fracture. Five hundred orthopedic surgeons, from various Spanish regions, were trained in different aspects of the study: inclusion and exclusion criteria, management of the risk factor questionnaire, and implementation of the Vogt questionnaire. The number of fracture cases was 1549 (31.79%). 528 Women (34.08%) had a single vertebral fracture, and 1021 (65.92%) had multiple vertebral fractures. The following factors were statistically significantly associated with vertebral fracture: age, late menarche, early menopause, diabetes mellitus, hyperparathyroidism, rheumatoid arthritis, height loss, daily physical activity, corticosteroid therapy, personal history of osteoporotic fracture and previous diagnosis of osteoporosis. The differences in Vogt score according to age and fracture status were statistically significant. The conclusion of the study is that vertebral osteoporotic fracture in the female Spanish population is frequent. The high prevalence in the Spanish population older than 60 years is probably related to malnutrition in the period from 1936 to 1952.
25013379 Targeting the sheddase activity of ADAM17 by an anti-ADAM17 antibody D1(A12) inhibits head 2014 A disintegrin and metalloproteinase 17 (ADAM17) regulates key cellular processes including proliferation and migration through the shedding of a diverse array of substrates such as epidermal growth factor receptor (EGFR) ligands. ADAM17 is implicated in the pathogenesis of many diseases including rheumatoid arthritis and cancers such as head and neck squamous cell carcinoma (HNSCC). As a central mediator of cellular events, overexpressed EGFR is a validated molecular target in HNSCC. However, EGFR inhibition constantly leads to tumour resistance. One possible mechanism of resistance is the activation of alternative EGFR family receptors and downstream pathways via the release of their ligands. Here, we report that treating human HNSCC cells in vitro with a human anti-ADAM17 inhibitory antibody, D1(A12), suppresses proliferation and motility in the absence or presence of the EGFR tyrosine kinase inhibitor (TKI) gefitinib. Treatment with D1(A12) decreases both the endogenous and the bradykinin (BK)-stimulated shedding of HER ligands, accompanied by a reduction in the phosphorylation of HER receptors and downstream signalling pathways including STAT3, AKT and ERK. Knockdown of ADAM17, but not ADAM10, also suppresses HNSCC cell proliferation and migration. Furthermore, we show that heregulin (HRG) and heparin-binding epidermal growth factor like growth factor (HB-EGF) predominantly participate in proliferation and migration, respectively. Taken together, these results demonstrate that D1(A12)-mediated inhibition of cell proliferation, motility, phosphorylation of HER receptors and downstream signalling is achieved via reduced shedding of ADAM17 ligands. These findings underscore the importance of ADAM17 and suggest that D1(A12) might be an effective targeted agent for treating EGFR TKI-resistant HNSCC.
24840642 Structural evaluation of BTK and PKCδ mediated phosphorylation of MAL at positions Tyr86 2014 Aug A number of diseases including sepsis, rheumatoid arthritis, diabetes, cardiovascular diseases and hyperinflammatory immune disorders have been associated with Toll like receptor (TLR) 2 and TLR4. Endogenous adaptor protein known as MyD88 adapter-like protein (MAL) bind exclusively to the cytosolic portions of TLR2 and TLR4 to initiate downstream signalling. Brutons tyrosine kinase (BTK) and protein kinase C delta (PKCδ) have been implicated to phosphorylate MAL and activate it to initiate downstream signalling. BTK has been associated with phosphorylation at positions Tyr86 and Tyr106, necessary for the activation of MAL but definite residual target of PKCδ in MAL is still to be explored. To produce a better understanding of the functional domains involved in the formation of MAL-kinase complexes, computer-aided studies were used to characterize the protein-protein interactions (PPIs) of phosphorylated BTK and PKCδ with MAL. Docking and physicochemical studies indicated that BTK was involved in close contact with Tyr86 and Tyr106 of MAL whereas PKCδ may phosphorylate Tyr106 only. Moreover, the electrostatics charge distribution of binding interfaces of BTK and PKCδ were distinct but compatible with respective regions of MAL. Our results implicate that position of Tyr86 is specifically phosphorylated by BTK whereas Tyr106 can be phosphorylated by competitive action of both BTK and PKCδ. Additionally, the residues of MAL which are necessary for interaction with TLR2, TLR4, MyD88 and SOCS-1 also play their roles in maintaining interaction with kinases and can be targeted in future to reduce TLR2 and TLR4 induced pathological responses.
24828490 Identification of heparin-binding EGF-like growth factor (HB-EGF) as a biomarker for lysop 2014 Lysophosphatidic acid (LPA) is a natural bioactive lipid with growth factor-like functions due to activation of a series of six G protein-coupled receptors (LPA₁₋₆). LPA receptor type 1 (LPA₁) signaling influences the pathophysiology of many diseases including cancer, obesity, rheumatoid arthritis, as well as lung, liver and kidney fibrosis. Therefore, LPA₁ is an attractive therapeutic target. However, most mammalian cells co-express multiple LPA receptors whose co-activation impairs the validation of target inhibition in patients because of missing LPA receptor-specific biomarkers. LPA₁ is known to induce IL-6 and IL-8 secretion, as also do LPA₂ and LPA₃. In this work, we first determined the LPA induced early-gene expression profile in three unrelated human cancer cell lines expressing different patterns of LPA receptors (PC3: LPA₁,₂,₆; MDA-MB-231: LPA1,2; MCF-7: LPA₂,₆). Among the set of genes upregulated by LPA only in LPA₁-expressing cells, we validated by QPCR and ELISA that upregulation of heparin-binding EGF-like growth factor (HB-EGF) was inhibited by LPA₁-₃ antagonists (Ki16425, Debio0719). Upregulation and downregulation of HB-EGF mRNA was confirmed in vitro in human MDA-B02 breast cancer cells stably overexpressing LPA₁ (MDA-B02/LPA₁) and downregulated for LPA₁ (MDA-B02/shLPA1), respectively. At a clinical level, we quantified the expression of LPA₁ and HB-EGF by QPCR in primary tumors of a cohort of 234 breast cancer patients and found a significantly higher expression of HB-EGF in breast tumors expressing high levels of LPA₁. We also generated human xenograph prostate tumors in mice injected with PC3 cells and found that a five-day treatment with Ki16425 significantly decreased both HB-EGF mRNA expression at the primary tumor site and circulating human HB-EGF concentrations in serum. All together our results demonstrate that HB-EGF is a new and relevant biomarker with potentially high value in quantifying LPA₁ activation state in patients receiving anti-LPA₁ therapies.
24316417 The orally available Btk inhibitor ibrutinib (PCI-32765) protects against osteoclast-media 2014 Mar Bone-resorbing osteoclasts play an essential role in normal bone homeostasis, as well as in various bone disorders such as osteoporosis and rheumatoid arthritis. Previously we showed that the Tec family of tyrosine kinases is essential for the differentiation of osteoclasts and the inhibition of Btk is a promising strategy for the prevention of the bone loss in osteoclast-associated bone disorders. Here we demonstrate that an orally available Btk inhibitor, ibrutinib (PCI-32765), suppresses osteoclastic bone resorption by inhibiting both osteoclast differentiation and function. Ibrutinib downregulated the expression of NFATc1, the key transcription factor for osteoclastogenesis, and disrupted the formation of the actin ring in mature osteoclasts. In addition, genome-wide screening revealed that Btk regulates the expression of the genes involved in osteoclast differentiation and function in both an NFATc1-dependent and -independent manner. Finally, we showed that ibrutinib administration ameliorated the bone loss that developed in a RANKL-induced osteoporosis mouse model. Thus, this study suggests ibrutinib to be a promising therapeutic agent for osteoclast-associated bone diseases.
24035274 Prostaglandin I2-IP signalling regulates human Th17 and Treg cell differentiation. 2013 Oct Prostaglandin I2 (PGI2) is an important immunoregulatory lipid mediator. In this study, we analysed the effects of the PGI2 analogue (Iloprost) on the differentiation of Th17 cells and Tregs from human naïve CD4(+) T cells. PGI2 receptors (IP) are expressed on human naïve CD4(+) T cells. Via IP binding, the PGI2 analogue decreased the proportion of Tregs and Foxp3 mRNA expression but increased the percentage of Th17 cells, RORC mRNA and IL-17A production. The regulatory effects of Iloprost correlated with elevated intracellular cAMP levels. The effects were mimicked by a cAMP agonist (db-cAMP) but attenuated by a protein kinase A inhibitor (H-89). STAT3 and STAT5 signalling play direct and crucial roles in the development of Th17 and Tregs, respectively. The PGI2 analogue enhanced the activation of STAT3 in response to IL-6, whereas it decreased STAT5 activation in response to IL-2. Moreover, db-cAMP imitated the above effects of Iloprost, which were weakened by H-89. These results demonstrate that the PGI2-IP interaction promoted the phosphorylation of STAT3 and reduced the phosphorylation of STAT5, likely via the upregulation of cAMP-PKA signalling, thus facilitated Th17 differentiation and suppressed Treg differentiation. Together with previous results, these data suggest that prostanoids play an important role in the pathogenesis of autoimmune diseases, such as rheumatoid arthritis.
23676463 Specific peripheral B cell tolerance defects in patients with multiple sclerosis. 2013 Jun Multiple sclerosis (MS) is a genetically mediated autoimmune disease of the central nervous system. B cells have recently emerged as major contributors to disease pathogenesis, but the mechanisms responsible for the loss of B cell tolerance in patients with MS are largely unknown. In healthy individuals, developing autoreactive B cells are removed from the repertoire at 2 tolerance checkpoints during early B cell development. Both of these central and peripheral B cell tolerance checkpoints are defective in patients with rheumatoid arthritis (RA) and type 1 diabetes (T1D). Here, we found that only the peripheral, but not the central, B cell tolerance checkpoint is defective in patients with MS. We show that this specific defect is accompanied by increased activation and homeostatic proliferation of mature naive B cells. Interestingly, all of these MS features parallel defects observed in FOXP3-deficient IPEX patients, who harbor nonfunctional Tregs. We demonstrate that in contrast to patients with RA or T1D, bone marrow central B cell selection in MS appears normal in most patients. In contrast, patients with MS suffer from a specific peripheral B cell tolerance defect that is potentially attributable to impaired Treg function and that leads to the accumulation of autoreactive B cell clones in their blood.
23355650 Haemodynamically irrelevant pericardial effusion is associated with increased mortality in 2013 May AIMS: Pericardial effusion (PE) is a common finding in cardiac patients with chronic heart failure. The prognostic relevance of a small, haemodynamically non-compromising PE in such patients, however, remains to be determined. METHODS AND RESULTS: All patients referred to our heart failure clinic and having a baseline echocardiography and follow-up clinical visits were included. Patients with a haemodynamically relevant PE, acute myo-/pericarditis, systemic sclerosis, rheumatoid arthritis, heart transplantation, heart surgery within the last 6 months or malignancies within the last 3 years were excluded. Patients with or without a haemodynamically irrelevant PE were compared regarding all-cause mortality as the primary and cardiovascular death or need for heart transplantation as secondary outcomes. A total of 897 patients (824 patients in the control vs. 73 patients in the PE group) were included. In the PE group, left ventricular ejection fraction (LVEF) was lower [31%, interquartile range (IQR): 18.0-45.0] than in controls (34%, IQR: 25.0-47.0; P = 0.04), while the end-systolic diameters of the left ventricle and the left atrium were larger (P = 0.01 and P = 0.001, respectively). Similarly, in patients with PE, the right ventricle (RV) systolic function was lower (P < 0.005 for both the fractional area change and the tricuspid annulus movement), the dimensions of RV and right atrium (RA) were larger (P < 0.05 for RV and P < 0.01 for RA), and the degree of tricuspid regurgitation was higher (P < 0.0001). Furthermore, in the PE group, the heart rate was higher (P < 0.001) and the leukocyte count as well as CRP values were increased (P = 0.004 and P < 0.0001, respectively); beta-blocker use was less frequent (P = 0.04), while spironolactone use was more frequent (P = 0.03). The overall survival was reduced in the PE group compared with controls (P = 0.02). Patients with PE were more likely to suffer cardiovascular death (1-year estimated event-free survival: 86 ± 5 vs. 95 ± 1%; P = 0.01) and to require heart transplantation (1-year estimated event-free survival: 88 ± 4 vs. 95 ± 1%; P = 0.009). A multivariate Cox proportional hazard model revealed the following independent predictors of mortality: (a) PE (P = 0.04, hazard ratio (HR): 1.95, 95% confidence interval (CI): 1.0-3.7), (b) age (P = 0.04, HR: 1.02, 95% CI: 1.0-1.04) and (c) LVEF <35% (P = 0.03, HR: 1.7, 95% CI: 1.1-2.8). CONCLUSION: In chronic heart failure, even minor PEs are associated with an increased risk of all-cause mortality, cardiac death, and need for transplantation.
25369825 Drug-induced subacute cutaneous lupus erythematosus associated with docetaxel chemotherapy 2014 Nov 5 BACKGROUND: Drug-induced subacute cutaneous lupus erythematosus is an uncommon disorder associated with the use of pharmacological agents including systemic chemotherapy. CASE PRESENTATION: We report a case of docetaxel-induced subacute cutaneous lupus erythematosus in a 60-year-old Caucasian female with Sjögren's syndrome diagnosed 2 months after receiving docetaxel as part of the adjuvant FEC-D (5-fluorouracil, epirubicin, cyclophosphamide, docetaxel) chemotherapy protocol for early stage breast cancer. Although the exact mechanisms behind the autoimmune response elicited by docetaxel are unclear, the involvement of anti-SSA/Ro antibodies has been implicated. CONCLUSION: This case highlights the symptom severity and clinical course of docetaxel-induced subacute cutaneous lupus erythematosus, and highlights the importance of recognizing this uncommon but potentially severe chemotherapy-associated cutaneous reaction.
25411202 A crucial role of RORγt in the development of spontaneous Sialadenitis-like Sjögren's sy 2015 Jan 1 The nuclear receptor retinoic acid-related orphan receptor (ROR)γt is required for the generation of Th17 cells, which are involved in various autoimmune diseases, including Sjögren's syndrome (SS). However, the pathological role of RORγt in SS remains to be elucidated. The present study was designed to clarify the role of RORγt in the pathogenesis of sialadenitis-like SS. Histological analysis of RORγt transgenic (Tg) mice was determined, and then Tg mice developed severe spontaneous sialadenitis-like SS. The analysis of infiltrating cells showed that most infiltrating cells were CD4(+) T cells. RORγt-overexpressing CD4(+) T cells induced sialadenitis as a result of transferred CD4(+) T cells from Tg mice into Rag2(-/-) mice. The examination of IL-17-deficient Tg mice indicated that IL-17 was not essential for the development of sialadenitis. The number of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells was significantly decreased in Tg mice, and CD25 expression and IL-2 stimulated STAT5 activation were inhibited in Treg cells. The inhibitory function of Treg cells of Tg mice was equal to that of wild-type mice in vitro. The abundant Treg cells of Tg mice could suppress the development of sialadenitis, but the reduced Treg cells of Tg mice could not inhibit the induction of sialadenitis in Rag2(-/-) mice transferred with effector cells from Tg mice. These results suggest that both RORγt-overexpressed CD4(+) T cells and reduced Treg cells might contribute to the development of SS-like sialadenitis.
23516437 Single-cell analysis reveals isotype-specific autoreactive B cell repertoires in Sjögren' 2013 Microengraving is a novel technology that uses an array of microfabricated subnanoliter wells to isolate and characterize secreted proteins from larger number of single cells. This printing technique permits the capture and characterization of secreted antibodies on glass slides. Here, we profiled the antigenic repertoires of B cells reacting against salivary gland tissues in Sjögren's syndrome (SjS), an autoimmune disease targeting the exocrine glands. Single-cell suspensions of spleen and cervical lymph node cells prepared from normal C57BL/6 and SjS-susceptible (SjS(s)) C57BL/6.NOD-AecAec2 mice were dispersed into subnanoliter wells (nanowells). Capture slides preincubated with mouse immunoglobulins were used for printing. Detection antibodies included fluorescence conjugated anti-IgG1, salivary gland lysates of C57BL/6 and SjS(s) mice. Results indicate an increase in the frequency of IgG1-secreting cells in the spleen of SjS(s) mice compared to C57BL/6 mice. Cells from the lymph node of SjS(s) mice yield higher instances of IgG1 reactive against salivary gland antigens than cells from the lymph nodes of C57BL/6 mice. These data demonstrate the isotype-specific reactivity of antibodies during the autoimmune process, and further reveals significant differences in the non-autoimmune and autoimmune antibody repertoires. These results support the generation of self-reactive B cell repertoires during the autoimmune process, at the same time, verifying that microengraving of single cells might allow for identification of novel biomarkers in SjS.
23853778 A protein nanofiber hydrogel for sensitive immunoassays. 2013 Sep 7 Amyloid-like protein nanofibers were assembled in vitro using a recombinant protein fusion, with yeast Sup35 and human SSB/La proteins as assembly units, where the length of the nanofibers was mostly between 100 and 400 nm. The protein nanofibers, hereafter referred to as Sup35-based protein nanofiber probes (SuPNPs), were used to sensitively detect anti-SSB/La antibodies [Sjögren's syndrome (SS)-specific marker]. After, the SuPNPs were vinylated and subsequently linked to acrylamide. The polymerization reaction with acrylamide formed a SuPNP-hydrogel with uniform porosity, where the SuPNPs were directly cross-linked to polyacrylamide. Alternatively, biotinylated SuPNPs (bt-SuPNP) were attached to a streptavidin-hydrogel, resulting in the formation of a bt-SuPNP-hydrogel. When both the SuPNP-hydrogel and bt-SuPNP-hydrogel were used as 3D assay platforms for the detection of anti-SSB/La antibodies in a buffer solution, the LODs (limit of detection) were found to be 10 pM for both, showing 100-fold enhancement in sensitivity compared to conventional 2D polystyrene (PS) plate-based assays. It seems that the exposed surface and uniform distribution of the SuPNPs within the 3D space of the porous hydrogel matrix interacted more effectively with the anti-SSB/La antibodies, leading to more sensitive detection. The equal sensitivity demonstrated by the SuPNP- and bt-SuPNP-hydrogels above indicates that the target binding activity of the SuPNPs remains unchanged when either directly cross-linked to the hydrogel or indirectly immobilized to the hydrogel via streptavidin. When used to detect anti-SSB/La antibodies in human serum, the SuPNP-hydrogel is 1000 times more sensitive than a 2D PS plate. It seems that non-specific adsorption of the serum proteins occurs heavily on the 2D PS plate. While diagnostic assays for Sjögren's syndrome were demonstrated as proof-of-concept in this study, the SuPNP-hydrogel can be generally applied for the sensitive and specific detection of many other disease markers.
24395332 Autoimmunity in the pathogenesis and treatment of keratoconjunctivitis sicca. 2014 Jan Dry eye is a chronic corneal disease that impacts the quality of life of many older adults. Keratoconjunctivitis sicca (KCS), a form of aqueous-deficient dry eye, is frequently associated with Sjögren's syndrome and mechanisms of autoimmunity. For KCS and other forms of dry eye, current treatments are limited, with many medications providing only symptomatic relief rather than targeting the pathophysiology of disease. Here, we review proposed mechanisms in the pathogenesis of autoimmune-based KCS: genetic susceptibility and disruptions in antigen recognition, immune response, and immune regulation. By understanding the mechanisms of immune dysfunction through basic science and translational research, potential drug targets can be identified. Finally, we discuss current dry eye therapies as well as promising new treatment options and drug therapy targets.
23665202 Spdef null mice lack conjunctival goblet cells and provide a model of dry eye. 2013 Jul Goblet cell numbers decrease within the conjunctival epithelium in drying and cicatrizing ocular surface diseases. Factors regulating goblet cell differentiation in conjunctival epithelium are unknown. Recent data indicate that the transcription factor SAM-pointed domain epithelial-specific transcription factor (Spdef) is essential for goblet cell differentiation in tracheobronchial and gastrointestinal epithelium of mice. Using Spdef(-/-) mice, we determined that Spdef is required for conjunctival goblet cell differentiation and that Spdef(-/-) mice, which lack conjunctival goblet cells, have significantly increased corneal surface fluorescein staining and tear volume, a phenotype consistent with dry eye. Microarray analysis of conjunctival epithelium in Spdef(-/-) mice revealed down-regulation of goblet cell-specific genes (Muc5ac, Tff1, Gcnt3). Up-regulated genes included epithelial cell differentiation/keratinization genes (Sprr2h, Tgm1) and proinflammatory genes (Il1-α, Il-1β, Tnf-α), all of which are up-regulated in dry eye. Interestingly, four Wnt pathway genes were down-regulated. SPDEF expression was significantly decreased in the conjunctival epithelium of Sjögren syndrome patients with dry eye and decreased goblet cell mucin expression. These data demonstrate that Spdef is required for conjunctival goblet cell differentiation and down-regulation of SPDEF may play a role in human dry eye with goblet cell loss. Spdef(-/-) mice have an ocular surface phenotype similar to that in moderate dry eye, providing a new, more convenient model for the disease.
25582995 [Autoimmune diseases and autoantibodies in pediatric patients and their first-degree relat 2015 May INTRODUCTION: Clinical manifestations of Immunoglobulin A Deficiency (IgAD) include recurrent infections, atopy and autoimmune diseases. However, to our knowledge, the concomitant evaluations of autoimmune diseases and autoantibodies in a cohort of IgAD patients with current age > 10 years-old and their relatives have not been assessed. OBJECTIVES: To evaluate autoimmune diseases and the presence of autoantibodies in IgAD patients and their first-degree relatives. METHODS: A cross-sectional study was performed in 34 IgAD patients (current age > 10 years-old) and their first-degree relatives. All of them were followed at a tertiary Brazilian primary immunodeficiency center: 27 children/adolescents and 7 of their first-degree relatives with a late diagnosis of IgAD. Autoimmune diseases and autoantibodies (antinuclear antibodies, rheumatoid factor, and anti-thyroglobulin, anti-thyroperoxidase and IgA class anti-endomysial antibodies) were also assessed. RESULTS: Autoimmune diseases (n=14) and/or autoantibodies (n=10, four of them with isolated autoantibodies) were observed in 18/34 (53%) of the patients and their relatives. The most common autoimmune diseases found were thyroiditis (18%), chronic arthritis (12%) and celiac disease (6%). The most frequent autoantibodies were antinuclear antibodies (2%), anti-thyroglobulin and/or anti-thyroperoxidase (24%). No significant differences were observed in the female gender, age at diagnosis and current age in IgAD patients with and without autoimmune diseases and/or presence of autoantibodies (p>0.05). The frequencies of primary immunodeficiency's in family, autoimmunity in family, atopy and recurrent infections were similar in both groups (p>0.05). CONCLUSION: Autoimmune diseases and autoantibodies were observed in IgAD patients during follow-up, reinforcing the necessity of a rigorous and continuous follow-up during adolescence and adulthood.
25002216 Does fracture affect the healing time or frequency of recurrence in a simple bone cyst of 2014 Oct BACKGROUND: Studies have focused on intramedullary nailing of femoral simple bone cysts but have not clarified the recurrence frequency or management of recurrent cysts. In particular, the affect of pathologic fractures on cyst healing, recurrence, and complications of treatment have not been reported. QUESTIONS/PURPOSES: We performed a retrospective comparative study to examine whether there were differences between simple bone cysts in the proximal femur nailed after pathologic fracture and those without pathologic fracture in terms of (1) healing time, (2) frequency and timing of recurrence, and (3) complications. METHODS: From 1995 to 2005, 54 patients diagnosed with femoral simple bone cysts were treated and followed for a minimum of 8 years. Flexible nails were inserted in a retrograde fashion in 25 patients with fractures and 29 patients without fractures. The healing period, degree of radiographic consolidation based on the criteria of Capanna et al., recurrence frequency, and final bony abnormalities were analyzed. The mean followups were 107 months (range, 96-124 months) and 103 months (range, 96-140 months) in the groups with and without fractures, respectively. With the numbers available, a post hoc calculation showed that this study had 80% power to detect a difference of 7 months of healing time as significant with a probability less than 0.05. RESULTS: With the numbers available, the mean healing period was not different between groups (25 versus 30 months in the groups with and without fractures, respectively; p = 0.16). Complete healing was observed at 19 versus 18 months, incomplete healing at 5 versus 8 months, and recurrence was observed in one and three patients in the groups with and without fractures, respectively. No differences were found in the distribution of healing grade based on the criteria of Capanna et al. A second surgery was performed using intramedullary nails in two patients with an open physis and compression hip screw fixation was performed in two patients with a closed physis. Finally, the recurrent cysts were classified as completely healed in three patients and incompletely healed in one. CONCLUSIONS: Whether a pathologic fracture had occurred before surgical treatment, intramedullary nailing of femoral simple bone cysts resulted in reliable healing, and the frequency of recurrence did not differ. Because this was a retrospective study, the optimal treatment for recurred cysts after intramedullary nailing should be further investigated through a comparative or prospective study.
25367998 Specialty drug spending trends among Medicare and Medicare Advantage enrollees, 2007-11. 2014 Nov Specialty pharmaceuticals include most injectable and biologic agents used to treat complex conditions such as rheumatoid arthritis, multiple sclerosis, and cancer. We analyzed trends in specialty drug spending among Medicare beneficiaries ages sixty-five and older using 2007-11 pharmacy claims data from a 20 percent sample of Medicare beneficiaries. Annual specialty drug spending per beneficiary who used specialty drugs increased considerably during the study period, from $2,641 to $8,976. However, specialty drugs accounted for only 6.7 percent of total drug spending per beneficiary in 2007 and 9.1 percent in 2011. Moreover, in 2011 cost-sharing reductions under the Affordable Care Act significantly reduced specialty drug users' out-of-pocket burden, which decreased 26 percent from 2010. Oral cancer agents accounted for a significant proportion of the increase in specialty drug spending among the study population. This suggests that the migration of specialty drug coverage from Medicare's Part B medical benefit to the Part D pharmacy benefit because of new treatment options may play an important role in specialty pharmacy trends. This shift is likely to continue as pharmaceutical innovations enable more specialty therapeutics to be self-administered and to be covered under the pharmacy instead of the medical benefit.
25096606 Chronic natural killer lymphoproliferative disorders: characteristics of an international 2014 Oct BACKGROUND: The 2008 World Health Organization (WHO) classification distinguishes three entities among the large granular lymphocytic leukemia (LGL leukemia): T-cell LGL leukemia (T-LGL leukemia), aggressive natural killer (NK) cell leukemia, and chronic NK lymphoproliferative disorders (LPD), the later considered as a provisional entity. Only a few and small cohorts of chronic NK LPD have been published. PATIENTS AND METHODS: We report here clinicobiological features collected retrospectively from 70 cases of chronic NK LPD, and compared with those of T-LGL leukemia. RESULTS: There were no statistical differences between chronic NK LPD and T-LGL leukemia concerning median age [61 years (range 23-82 years)], organomegaly (26%), associated autoimmune diseases (24%), and associated hematological malignancies (11%). Patients with chronic NK LPD were significantly less symptomatic (49% versus 18%, P < 0.001) and the association with rheumatoid arthritis was more rarely observed (7% versus 17%, P = 0.03). The neutropenia (<0.5 × 10(9)/l) was less severe in chronic NK LPD (33% versus 61%, P < 0.001) without difference in the rate of recurrent infections. STAT3 mutation was detected in 12% of the cohort, which is lower than the frequency observed in T-LGL leukemia. Thirty-seven percent of the patients required specific therapy. Good results were obtained with cyclophosphamide. Overall and complete response rates were, respectively, 69% and 56%. Overall survival was 94% at 5 years. CONCLUSION: This study suggests very high similarities between chronic NK LPD and T-LGL leukemias. Since chronic NK LPD is still a provisional entity, our findings should be helpful when considering further revisions of the WHO classification.
24451241 Hormone replacement therapy and mid-term implant survival following knee or hip arthroplas 2015 Mar OBJECTIVES: Osteolysis and subsequent prosthesis loosening is the most common cause for revision following total knee arthroplasty (TKA) or total hip arthroplasty (THA). Hormone replacement therapy (HRT) could reduce osteolysis through its antiresorptive effects. We studied whether HRT use is associated with reduced revision rates in a community-based cohort of women undergoing TKA or THA for osteoarthritis. METHODS: Female participants in the General Practice Research Database undergoing a primary TKA or THA from 1986 to 2006 were included. We excluded patients aged <40 years at the date of primary, and those with a history of previous hip fracture or rheumatoid arthritis. Women with at least 6 months of HRT were identified as HRT users. We further explored the associations among HRT use of ≥12 months, adherence (medication possession ratio) and cumulative use and revision risk. Cox models were fitted to model implant survival in years. Propensity score matching was used to control for confounding. RESULTS: We matched 2700 HRT users to 8100 non-users, observed for a median (IQR) of 3.3 (1.5-6.1) years after TKA/THA. HR for HRT ≥6 months was 0.62 (95% CI 0.41 to 0.94), whereas HR for ≥12 months was 0.48 (0.29 to 0.78). Higher adherence and therapy duration were associated with further reductions in revision rates. Preoperative HRT appeared unrelated to implant survival. CONCLUSIONS: HRT use is associated with an almost 40% reduction in revision rates after a TKA/THA. These findings require replication in external cohorts and experimental studies.
25295265 IGF-1 and ADMA levels are inversely correlated in nondiabetic ankylosing spondylitis patie 2014 Like rheumatoid arthritis, ankylosing spondylitis (AS) is also an inflammatory disease associated with accelerated atherosclerosis and the presence of metabolic syndrome (MeS) features. AS patients often display osteoporosis as well as new bone formation. Insulin-like growth factor 1 (IGF-1) is a protein involved in both inflammation and bone metabolism. In the present study we assessed whether disease activity, systemic inflammation, MeS features, adipokines, and biomarkers of endothelial activation were associated with IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3) levels in a series of 30 nondiabetic AS patients without CV disease undergoing TNF-α antagonist-infliximab therapy. All determinations were made in the fasting state, immediately before an infliximab infusion. Although no association of IGF-1 and IGFBP-3 levels with angiopoietin-2 or osteopontin was found, an inverse correlation between IGF-1 levels and asymmetric dimethylarginine (ADMA), an endogenous endothelial nitric oxide synthase inhibitor that impairs nitric oxide production and secretion promoting endothelial dysfunction, was found (r=-0.397; P=0.04). However, no significant association was found between IGF-1 and IGFBP-3 levels and disease activity, systemic inflammation, metabolic syndrome features, or adipokines. In conclusion, in nondiabetic patients with AS undergoing periodic anti-TNF-α therapy, IGF-1 and ADMA are inversely correlated.