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ID PMID Title PublicationDate abstract
20704604 Chronic necrotizing pulmonary aspergillosis in a patient treated with a tumor necrosis fac 2010 Aug Tumor necrosis factor (TNF)-alpha is a pro-inflammatory cytokine that plays an important role in the pathogenesis of a variety of autoimmune diseases. TNF-alpha inhibitors have been shown to offer clinical benefits in the treatment of autoimmune and inflammatory disorders, including rheumatoid arthritis, ankylosing spondylitis (AS), and Crohn's disease. Occasionally, these agents have been associated with infectious complications because of their immunosuppressive activity. Globally, several cases of infections associated with TNF-alpha inhibitors have been reported. However, Aspergillus infection associated with etanercept is very rare. We report a case of chronic necrotizing pulmonary aspergillosis in a 51-year-old man with AS that developed after treatment with etanercept.
20610201 Isolated medial incisional approach to subtalar and talonavicular arthrodesis. 2010 Jul Triple arthrodesis is commonly used to correct complex deformity with hindfoot valgus. The authors use an isolated medial incisional approach for subtalar and talonavicular joint arthrodesis to correct hindfoot deformity, including high degrees of hindfoot valgus. To assess outcomes achieved with this approach, we reviewed the records of 45 patients from the practices of 5 surgeons. Independent variables evaluated included patient age, primary pathology, use of biologic agents, operative time, time to union, and complications. The median patient age was 57 years (range, 14-78 years). Pathology leading to fusion included 27 (60%) posterior tibial tendon dysfunction, 6 (13.3%) tarsal coalition, 7 (5.5%) degenerative joint disease, 2 (4.4%) rheumatoid arthritis, and 1 (2.2%) each, with Charcot neuroarthropathy, multiple sclerosis, and poliomyelitis. Orthobiological materials were used in 27 (60.0%) of the patients. The median duration of surgery was 87 minutes (range, 65-164 minutes), and the median time to successful arthrodesis was 8 weeks (range, 6-20 weeks). A complication was observed in 6 (13.3%) of the patients, including 1 each of the following: painful calcaneal-cuboid joint, talar fracture, incision dehiscence, poor exposure that required abandonment of the procedure, elevated first ray, and painful fixation. None of the patients experienced a nonunion or an adverse event related to the medial neurovascular structures. Based on our experience with the procedure, the single medial-incision subtalar and talonavicular joint arthrodesis is a useful alternative to triple arthrodesis for the correction of hindfoot valgus deformity.
20575393 [Effects of triptolide on cell proliferation and regulation of Ras-MAPKs pathway in synovi 2010 Apr OBJECTIVE: To investigate the effects of triptolide on proliferation and regulation of ras-MAPKs pathway in human fibroblast-like synoviocytes of rheumatoid arthritis (RA-HFLS) treated with tumor necrosis factor (TNF-alpha). METHOD: RA-HFLS were cultured with TNF-alpha in the presence or absence of variable doses of triptolide (0.28, 2.8, 28, 140 nmol x L(-1)) in vitro. Cell proliferation was evaluated by MTS assay. The phosphorylation status of Ras-MAPKs-associated proteins (Ras, p-P38, p-ERK and p-JNK) were detected by Western blot analysis. RESULT: Triptolide could obviously decrease the RA-HFLS viability in a dose-dependent manner and the inhibition ratio was 0.28%, 5.05%, 30.83% and 43.77% respectively. In addition, triptolide could also suppressed the expression of Ras, p-P38, p-ERK and p-JNK. CONCLUSION: Triptolide has an notable inhibiting effect on proliferation of RA-HFLS and the molecule mechanism is due in part to the direct suppression of abnormal activation of Ras-MAPKs pathway.
22457695 Na, K-ATPase: Ubiquitous Multifunctional Transmembrane Protein and its Relevance to Variou 2010 Feb The Na(+), K(+)-ATPase (NKA) is an ubiquitous enzyme consisting of α, β and γ subunits, and is responsible for the creation and maintenance of the Na(+) and K(+) gradients across the cell membrane by transporting 3 Na(+) out and 2 K(+) into the cell. Sodium pump regulation is tissue as well as isoform specific. Intracellular messengers differentially regulate the activity of the individual NKA isozymes. Regulation of specific NKA isozymes gives cells the ability to precisely coordinate NKA activity to their physiological requirements. It is the only known receptor for the cardiac glycosides used to treat congestive heart failure and cardiac arrhythmias. Endogenous ligands structurally similar to cardiac glycosides may act as natural regulators of the sodium pump in heart and other tissues. Identification of naturally occurring regulators of  NKA could initiate the discovery of new hormone-like control systems involved in the etiology of selected disease processes, hence the importance of understanding the relation of the sodium pump and its ligands to disease. Diabetes has a marked effect on the metabolism of a variety of tissues and because the NKA is critical for the membrane potential and many transports, a change in its activity in diabetes would have profound consequence in these tissues. NKA is also involved in hypertension, salt balance, cardiovascular and renal disorders, sperm capacitation, cell volume regulation, apoptosis, rheumatoid arthritis, sepsis, neurological disorders, lung edema clearance and preeclampsia. NKA activity and expression in the collecting duct of kidney are modulated physiologically by hormones like aldosterone, vasopressin, and insulin. NKA enzyme activity and subunit levels are reduced in carcinoma, NKA-β levels were highly reduced in an invasive form of human renal clear cell carcinoma, androgen-dependent prostate cancer, in early stages of urothelial cancer, as well as in poorly differentiated, highly motile carcinoma cell lines obtained from various tissues suggesting a functional link between reduced NKA-β expression and cancer progression. It could be a target for the development of anticancer drugs as it serves as a signal transducer, it is a player in cell adhesion and its aberrant expression and activity are implicated in the development and progression of different cancers. KEYWORDS: Na(+), K(+)-ATPase (NKA); Cardiotonic steroids (CTS); Diabetes; Hypertension; Cardiovascular and renal disorders; Signal transducer; Anticancer drugs.
19379516 Differential gene expression in the salivary gland during development and onset of xerosto 2009 INTRODUCTION: Recently, we reported the development of the C57BL/6.NOD-Aec1Aec2 mouse that carries two genetic intervals derived from the non-obese diabetic (NOD) mouse capable of conferring Sjögren's syndrome (SjS)-like disease in SjS-non-susceptible C57BL/6 mice. In an attempt to define the molecular bases underlying the onset of stomatitis sicca (xerostomia) in this C57BL/6.NOD-Aec1Aec2 mouse model, we have carried out a study using genomic microarray technology. METHODS: By means of oligonucleotide microarrays, gene expression profiles of salivary glands at 4, 8, 12, 16, and 20 weeks of age were generated for C57BL/6.NOD-Aec1Aec2 male mice. Using Linear Models for Microarray Analysis and B-statistics software, 480 genes were identified as being differentially expressed (P < 0.01 and Q < 0.0001) during the development of SjS-like disease in the salivary glands. RESULTS: The 480 genes could be arranged into four clusters, with each cluster defining a unique pattern of temporal expression, while the individual genes within each cluster could be grouped according to related biological functions. By means of pair-wise analysis, temporal changes in transcript expressions provided profiles indicating that many additional genes are differentially expressed at specific time points during the development of disease. Multiple genes reportedly showing an association with autoimmunity and/or SjS, in either humans or mouse models, were found to exhibit differential expressions, both quantitatively and temporally. Selecting various families of genes associated with specific functions (for example, antibody production, complement, and chemokines), we noted that only a limited number of family members showed differential expressions and these correlated with specific phases of disease. CONCLUSIONS: Taking advantage of known functions of these genes, investigators can construct interactive gene pathways, leading to modeling of possible underlying events inducing salivary gland dysfunction. Thus, these different approaches to analyzing microarray data permit the identification of multiple sets of genes of interest whose expressions and expression profiles may correlate with molecular mechanisms, signaling pathways, and/or immunological processes involved in the development and onset of SjS.
18713786 Quantitative assessment of antibodies to ribonucleoproteins in primary Sjögren syndrome: 2009 Jul OBJECTIVES: To assess the added value of using a radioligand assay (RLA) compared with ELISA to detect antibodies to SSA, SSB and RNP, and to analyse the correlation between autoantibody levels, B-cell biomarkers and disease activity. PATIENTS AND METHODS: Antibodies to SSA, SSB and RNP were assessed in 127 patients with primary Sjögren syndrome (pSS) using an RLA and ELISA. In parallel, measures of B-cell activation were determined including serum levels of B-cell-activating factor of the tumour necrosis factor family or BLyS (BAFF). RESULTS: RLA was more sensitive than ELISA for the detection of antibodies to SSB (54% of positive samples versus 37%, respectively) and antibodies to RNP (9% vs 3%). No difference was seen for the sensitivity of detection of antibodies to SSA. Anti-SSA and anti-SSB levels were correlated with both techniques. Mean levels of antibodies to SSA were significantly higher in patients presenting antibodies to both SSA and SSB than in those exhibiting antibodies to SSA only (RLA: mean (SEM) anti-SSA levels 2343 (158) cpm vs 1348 (286) cpm, respectively, p = 0.02; ELISA: 6.8 (0.8) vs 3.8 (0.4), respectively, p = 0.003). Levels of antibodies to SSA and SSB significantly correlated with those of circulating BAFF (r = 0.4, p = 0.004 and r = 0.6, p<0.001, respectively) and with B-cell biomarkers, including levels of gammaglobulins, beta(2) microglobulin and rheumatoid factor. CONCLUSION: RLA allowed a quantitative and more sensitive detection of antibodies to SSB and RNP in pSS. Quantitative assessment of autoantibodies might disclose a biomarker of disease activity and enable further insight into the pathogenesis of the spreading of the autoantibody response.
19376597 Case report: aplasia of the lacrimal and major salivary glands (ALSG). 2009 Jun Aplasia of the lacrimal and major salivary glands (ALSG) is a rare, autosomal dominant disorder that is characterized by aplasia, atresia, or hypoplasia of the lacrimal and salivary glands. Affected patients may have aplasia or hypoplasia or minimal involvement of these glands, as there is considerable variation in expressivity [M. Entesarian, et al., Mutations in the gene encoding fibroblast growth factor 10 are associated with aplasia of lacrimal and salivary glands, Nat. Genet. 37 (2) (2005) 125-127]. The underlying cause has been linked to "loss of function" mutations in the fibroblast growth factor 10 (FGF10) gene [M. Entesarian, et al., FGF10 missense mutations in aplasia of lacrimal and salivary glands (ALSG), Eur. J. Hum. Genet. 15 (3) (2007) 379-382]. Lacrimal gland absence or hypoplasia causes symptoms such as irritable eyes, recurrent eye infections and epiphora. Symptoms associated with hypoplasia or aplasia of the major salivary glands include xerostomia, oral inflammation, dental caries and dental erosion. Other clinical signs of this disorder include atresia of nasolacrimal duct and absence of the lacrimal puncta. Unfortunately, genetic testing for this disorder is currently unavailable. However, MRI is an excellent alternative means for evaluating this disorder and also for ruling out other possible structural defects contributing to patients, symptoms. We present a case report of ALSG as an extremely rare, yet important alternative diagnosis in cases with symptoms and signs suggestive of Sjögren's syndrome.
20464362 [Salivary gland stem cells : Can they restore radiation-induced salivary gland dysfunction 2010 Jun Adult stem cells are actively investigated in the fields of regenerative medicine and tissue engineering, as they exhibit specific characteristics that make them promising candidates for cellular therapies. Depending on their tissue of origin these characteristics include long-term proliferation and the capacity to differentiate into various cell types. To date adult stem cells have been isolated from a multitude of tissues. Non-embryogenic adult tissues contain only small numbers of such stem cells and the derivation of such tissues can cause comorbidities. Therefore, there is ongoing interest in the identification and characterisation of novel cell sources for stem cell isolation and characterisation.Recently, salivary gland tissue has also been explored as a possible source of stem cells, first in animals and later in humans. Such salivary gland-derived stem cells might be useful in the treatment of radiation-induced salivary gland hypofunction, and possibly also in other diseases with loss of acinar cells, such as sequelae of radio iodine treatment or Sjögren's disease.In this paper we review the current status of salivary gland stem cell biology and application and discuss the possible role of stem cells in the development of novel therapies for salivary gland dysfunctions such as postradiogenic xerostomia.
20601088 Stem cells in the spleen: therapeutic potential for Sjogren's syndrome, type I diabetes, a 2010 Oct The view of the spleen as an unnecessary organ has been shattered. The evidence shows the spleen to be a source of naturally-occurring multipotent stem cells with possibly pluripotent potential. The stem cells are sequestered in the spleen of not only of animals but also of normal human adults. The reservoir of cells is set for differentiation and they need not be manipulated in vitro or ex vivo before autologous or heterologous use. Splenic stem cells, of Hox11 lineage, have been found in disease or injury to differentiate into pancreatic islets, salivary epithelial cells and osteoblast-like cells, cranial neurons, cochlea, lymphocytes, and more differentiated immune cells that repair injured heart cells. Injury or disease in target tissues induces these stem cells, still in the spleen, to upregulate the same embryonic transcription factors artificially introduced into induced pluripotent stem cells (iPS). Splenic stem cells may have broad pluripotent potential, but unlike iPS cells, possess low oncogenic risk.
20446609 [Mucosa-associated lymphoid tissue lymphoma in the thymus with multiple amyloid nodules in 2010 May Here, we present a case of mucosa-associated lymphoid tissue (MALT) lymphoma in the thymus with multiple amyloid nodules in both lung. A 66-year-old woman was incidentally found to have an abnormal shadow on mass-screening chest roentgenogram. A chest computed tomography (CT) demonstrated a mass of 50 mm in diameter with a smooth margin adjacent to the heart in the anterior mediastinum and multiple small nodules in both lung. As a differential diagnosis, thymic carcinoma with multiple lung metastases was firstly considered from these clinical informations. To make a definite diagnosis, the operation via a thoracoscopy was done. As a result, it turned out that pulmonary nodules were amyloidosis and the thymic tumor was MALT lymphoma. Postoperative course was uneventful and she was treated with chemoradiotherapy. In addition, she was diagnosed with Sjögren's syndrome 1 and half years later. Four years later the patient has been well without recurrence.
18538829 Antibody clustering helps refine lupus prognosis. 2009 Aug OBJECTIVE: Our aim was to investigate a possible association between patterns of anti-dsDNA antibody isotypes (IgG, IgM, and IgA), rheumatoid factor (RF) isotypes (IgG, IgM, IgA), and IgG anti-C reactive protein (CRP) and systemic lupus erythematosus (SLE) disease activity (SLEDAI). METHODS: Our study group included 98 patients, 86 women and 12 men, with a mean SLEDAI score of 7.9 +/- 4.1. We divided the patients into 4 groups by the serum anti-dsDNA antibody isotype intensity level. RESULTS: We found that patients in group 1 (IgG > IgM, 42 patients) had a statistically significantly higher SLEDAI score than group 2 (IgG < IgM, 13 patients) (10.57 +/- 4.62 versus 5.6 +/- 4, P = 0.0012), group 3 (IgG = IgM, 8 patients) (10.57 +/- 4.62 versus 6.2 +/- 1.98, P = 0.04), and group 4 (none, 35 patients) (10.57 +/- 4.62 versus 6 +/- 1.5, P = 0.0001). SLE patients with IgG RF or IgM RF isotype present had a significantly higher SLEDAI score compared with those without IgG RF or IgM RF (10.57 +/- 4.8 versus 7.6 +/- 4.1, P = 0.03, 10.6 +/- 5 versus 7.6 +/- 3.9, P = 0.046). The presence of IgA RF isotype was not associated with a higher SLEDAI score. IgG anti-CRP did not correlate differentially with SLEDAI scores. CONCLUSIONS: A combination of high-titer IgG anti-dsDNA with a positive RF of IgM isotype may serve as a marker for more active SLE.
22842318 Analysis of patients with post-chemotherapy arthralgia and arthritis in breast cancer. 2010 May OBJECTIVE: Evaluate the characteristics of arthropathy and musculoskeletal pain after chemotherapy in patients with breast cancer. MATERIALS AND METHODS: In this study, we evaluate the characteristics of 15 patients with joint symptoms after receiving chemotherapy for breast cancer. Demographic information including sex, age, time of rheumatologic findings after starting of chemotherapy, and time of improvement after starting of medication, and laboratory findings detected for each patient. RESULTS: Patients comprised 15 women with mean age 43.4 ± 10.6 years that received classic chemotherapy for breast cancer according to stage of disease including cyclophosphamide, and tamoxifen. Joint symptoms usually began about 6 months after the first session of chemotherapy. Patients had an average of 2 tender joints and 1 hour of morning stiffness. None of patients were positive for anti-nuclear antibody, and just 1 patient was positive for rheumatoid factor. Non-steroidal anti-inflammatory drugs, disease modifying anti-rheumatic drugs (DMARD), corticosteroids, and venlafaxine were prescribed. 5 patients did not show an improvement and were also given low dose oral corticosteroids. Follow-up was available for all patients. 13 patients showed favorable responses, characterized by a significant decrease (more than 50%) in morning stiffness, pain, and tender joint counts after a mean of 3 months' treatment. 9 patients had complete resolution of symptoms and stopped all medications. CONCLUSION: Chemotherapy-related arthropathy is not rare, and the prognosis is fairly good with early treatment using NSAID, DMARD, and corticosteroids.
19494274 The immunoregulatory enzyme IDO paradoxically drives B cell-mediated autoimmunity. 2009 Jun 15 Rheumatoid arthritis (RA) is a chronic and debilitating inflammatory autoimmune disease of unknown etiology. As with a variety of autoimmune disorders, evidence of elevated tryptophan catabolism has been detected in RA patients indicative of activation of the immunomodulatory enzyme IDO. However, the role that IDO plays in the disease process is not well understood. The conceptualization that IDO acts solely to suppress effector T cell activation has led to the general assumption that inhibition of IDO activity should exacerbate autoimmune disorders. Recent results in cancer models, however, suggest a more complex role for IDO as an integral component of the inflammatory microenvironment necessary for supporting tumor outgrowth. This has led us to investigate the involvement of IDO in the pathological inflammation associated with RA. Using the K/BxN murine RA model and IDO inhibitor 1-methyl-tryptophan, we found that inhibiting IDO activity had the unexpected consequence of ameliorating, rather than exacerbating arthritis symptoms. 1-Methyl tryptophan treatment led to decreased autoantibody titers, reduced levels of inflammatory cytokines, and an attenuated disease course. This alleviation of arthritis was not due to an altered T cell response, but rather resulted from a diminished autoreactive B cell response, thus demonstrating a previously unappreciated role for IDO in stimulating B cell responses. Our findings raise the question of how an immunosuppressive enzyme can paradoxically drive autoimmunity. We suggest that IDO is not simply immunosuppressive, but rather plays a more complex role in modulating inflammatory responses, in particular those that are driven by autoreactive B cells.
20575286 [Radiographic imaging feature and differential diagnosis of early femoral head necrosis]. 2010 May OBJECTIVE: To study early femoral head necrosis radiographic imaging features to provide objective basis for the clinical differential diagnosis and therapeutic schedule's choice. METHODS: Ninty-one patients with femur head necrosis of ARCO stage I and II whom were diagnosed by clinic and MRI and treated from March 2007 to June 2008 were analyzed retrospectively. There were 32 males and 59 females with an average age of (34.83 +/- 9.57) years ranging from 21 to 60 years. The course of disease were from 2 to 12 months. There were 17 cases of unilateral and 74 of bilateral; 48 cases caused by steroid, 35 cases by alcohol and 8 cases for unknown reasons. The images of X-ray, CT and MRI of femoral head were analyzed to summarize the characteristic and to distinguish with the imaging of similar osteonecrosis. RESULTS: Ninety-one cases had linear low signal on T1WI in weight-bearing area of femoral head and high signal of the "dual taxation" on T2WI. But the shapes had different characteristics. There were 36 cases (39.56%) of line type shapes, 28 cases (30.77%) of oval shapes, 14 cases (15.38%) of map-like shapes, 13 cases (14.29%) of wedge shapes. The X-rays of the disease similar to bone necrosis including primary hip osteoarthritis, developmental dysplasia of hip arthritis, femoral head epiphysitis (coxa plana), rheumatoid hip arthritis, hip arthritis of ankylosing spondylitis, transitional synovitis of hip joint, femoral head bone marrow edema etc, had the similar performance to femur head necrosis like cystic changes, joint space narrowing, femoral head deformation. MRI performance had their own characteristics. CONCLUSION: Mastering the image features of the early femoral head necrosis will help the early diagnosis and treatment of hip joint necrosis disease.
21151480 NIK stabilization in osteoclasts results in osteoporosis and enhanced inflammatory osteoly 2010 Nov 8 BACKGROUND: Maintenance of healthy bone requires the balanced activities of osteoclasts (OCs), which resorb bone, and osteoblasts, which build bone. Disproportionate action of OCs is responsible for the bone loss associated with postmenopausal osteoporosis and rheumatoid arthritis. NF-κB inducing kinase (NIK) controls activation of the alternative NF-κB pathway, a critical pathway for OC differentiation. Under basal conditions, TRAF3-mediated NIK degradation prevents downstream signaling, and disruption of the NIK:TRAF3 interaction stabilizes NIK leading to constitutive activation of the alternative NF-κB pathway. METHODOLOGY/PRINCIPAL FINDINGS: Using transgenic mice with OC-lineage expression of NIK lacking its TRAF3 binding domain (NT3), we now find that alternative NF-κB activation enhances not only OC differentiation but also OC function. Activating NT3 with either lysozyme M Cre or cathepsinK Cre causes high turnover osteoporosis with increased activity of OCs and osteoblasts. In vitro, NT3-expressing precursors form OCs more quickly and at lower doses of RANKL. When cultured on bone, they exhibit larger actin rings and increased resorptive activity. OC-specific NT3 transgenic mice also have an exaggerated osteolytic response to the serum transfer model of arthritis. CONCLUSIONS: Constitutive activation of NIK drives enhanced osteoclastogenesis and bone resorption, both in basal conditions and in response to inflammatory stimuli.
18336875 Medication adherence of patients with selected rheumatic conditions: a systematic review o 2009 Apr OBJECTIVE: Nonadherence with medication treatment has been found to occur in large proportions of patients with a broad range of chronic conditions. Our aim was to perform a systematic review of the literature examining adherence with treatments for inflammatory rheumatic conditions to assess the magnitude of the problem in this patient population. METHODS: A MEDLINE search of English language literature was performed to identify studies published between January 1, 1985 and November 30, 2007 that evaluated adherence with chronic medications needed in the treatment of rheumatic conditions. RESULTS: A total of 20 articles met the criteria for evaluation, the majority of which focused on the treatment of rheumatoid arthritis. Most of the studies examined the use of nonsteroidal anti-inflammatory medications and disease-modifying antirheumatic drugs. Adherence was assessed based on self-report, pill counts, pharmacy dispensings, openings of pill containers using electronic devices, laboratory assays, and physician assessment. Adherence varied greatly based on the adherence measure used, arthritic condition evaluated, and medication under study. Overall, the highest rates of adherence were based on self-reports for a wide variety of medications and conditions (range of persons reporting adherence was 30 to 99%), while the lowest adherence rates were for allopurinol based on pharmacy dispensings (18-26%). CONCLUSIONS: Adherence has not been widely examined for most chronic inflammatory rheumatic conditions and the few studies that exist used different definitions and populations, thus limiting any conclusions. However, the current literature does suggest that nonadherence is a substantial problem.
21105711 Discovery of CP-690,550: a potent and selective Janus kinase (JAK) inhibitor for the treat 2010 Dec 23 There is a critical need for safer and more convenient treatments for organ transplant rejection and autoimmune disorders such as rheumatoid arthritis. Janus tyrosine kinases (JAK1, JAK3) are expressed in lymphoid cells and are involved in the signaling of multiple cytokines important for various T cell functions. Blockade of the JAK1/JAK3-STAT pathway with a small molecule was anticipated to provide therapeutic immunosuppression/immunomodulation. The Pfizer compound library was screened against the catalytic domain of JAK3 resulting in the identification of a pyrrolopyrimidine-based series of inhibitors represented by CP-352,664 (2a). Synthetic analogues of 2a were screened against the JAK enzymes and evaluated in an IL-2 induced T cell blast proliferation assay. Select compounds were evaluated in rodent efficacy models of allograft rejection and destructive inflammatory arthritis. Optimization within this chemical series led to identification of CP-690,550 1, a potential first-in-class JAK inhibitor for treatment of autoimmune diseases and organ transplant rejection.
21165350 Treatment of pulmonary hypertension in patients with connective tissue disease and interst 2010 Nov BACKGROUND: Pulmonary hypertension (PH) in patients with connective tissue disease (CTD) can occur in isolation or concomitantly with interstitial lung disease (ILD). Targeted therapies for PH can mitigate clinical deterioration in CTD patients with isolated PH; however, the effect of these therapies in CTD patients with PH and ILD (CTD-PH-ILD) are poorly characterized. OBJECTIVE: To investigate outcomes following long-term treatment of PH in patients with CTD-PH-ILD.  METHODS:   A retrospective evaluation of 13 CTD-PH-ILD patients who were treated with bosentan, sildenafil or bosentan plus sildenafil, was conducted. Immunosuppressants were prescribed as indicated. Patients underwent pulmonary function testing and assessment of 6 min walk distance at the time of treatment initiation and during follow-up. Patients were followed until time of death, lung transplantation or the end of the study. Kaplan-Meier estimates of survival were calculated and log-rank testing was used to analyze survival differences according to CTD subtype. RESULTS: Thirteen patients (seven with systemic sclerosis [SSc], four with overlap syndrome, and two with rheumatoid arthritis) were followed for a mean (± SD) duration of 33.8±21.7 months. The survival estimate at a median duration of 34 months was 85%; two patients with SSc died. Mortality rates were greater among patients with SSc versus other CTD subtypes (P=0.04). No changes from baseline to follow-up in mean forced vital capacity or exercise capacity, and no treatment-related toxicity, were observed. CONCLUSION: Treatment using PH-specific therapies in patients with CTD, PH and ILD was well tolerated. Further studies to investigate the efficacy of PH-specific therapies in CTD-PH-ILD patients are warranted.
19950291 Depletion of functionally active CD20+ T cells by rituximab treatment. 2009 Dec OBJECTIVE: Rituximab is a therapeutic anti-CD20 antibody used for in vivo depletion of B cells in proliferative and autoimmune diseases. However, the mechanisms of action are not fully understood, since not all of the therapy-mediated effects can be explained by the depletion of antibody-secreting cells. In addition to B cells, there is also a small population of T cells coexpressing CD20 in all individuals. This study was conducted to examine the phenotype and function of CD3+CD20+ T cells in patients with rheumatoid arthritis (RA) and healthy controls. METHODS: The phenotype and apoptosis of peripheral blood mononuclear cells from healthy donors and RA patients were examined by 4-color fluorescence-activated cell sorting analyses. Cytokine production was determined by intracellular staining and measurement of cytokines in the supernatants. Proliferation of sorted T cell populations was analyzed using 3H-thymidine uptake assays. RESULTS: In healthy individuals, 0.1-6.8% of peripheral blood T cells (mean 1.6%; n=142) coexpressed CD20, which was not significantly different from that in the peripheral blood of RA patients, in whom 0.4-2.6% of T cells (mean 1.2%; n=27) were CD20+. During rituximab therapy, the CD20+ T cells along with the B cells were eliminated from the RA peripheral blood. Among the CD20+ T cells, 45% coexpressed CD8 and 55% coexpressed CD4. Polyclonal CD3+CD20+ cells were functionally characterized by constitutive cytokine production (i.e., interleukin-1beta and tumor necrosis factor alpha), a low proliferative capacity, a high activation state, and enhanced susceptibility to apoptosis. CONCLUSION: These findings suggest that CD20+ T cells represent a terminally differentiated cell type with immune-regulatory and proinflammatory capacities. Depletion of CD20+ T cells may be an additional mechanism by which anti-CD20 therapy functions in patients with RA.
19950288 Glucocorticoids increase alpha5 integrin expression and adhesion of synovial fibroblasts b 2009 Dec OBJECTIVE: In rheumatoid arthritis (RA), integrins mediate cell adhesion, migration, and invasion, and their expression is regulated by cytokines and growth factors. The aim of this study was to investigate whether hormones such as cortisol or other steroids can influence integrin expression and function in the synovial cells of patients with RA. METHODS: We performed immunofluorescence and fluorescence-activated cell sorting analyses to quantify surface integrin levels. Adhesion and migration assays were performed to study the function of synovial fibroblasts (SFs). ERK activation was measured by cellular activation of a signaling enzyme-linked immunosorbent assay. Invasion of SFs into cartilage was determined in the SCID mouse coimplantation model of RA in vivo. RESULTS: In RA, expression of integrin subunits alpha5, alphav, and beta1 was higher at the site of invasion compared with the sublining zone. Testosterone and 17beta-estradiol had no influence on integrin levels, but cortisol up-regulated expression of the alpha5 subunit in a time-dependent and dose-dependent manner. In addition, cortisol increased the adhesion of SFs to fibronectin and inhibited ERK signaling upon integrin activation or upon stimulation with tumor necrosis factor. Small interfering RNA or a neutralizing antibody to alpha5 integrin increased SF migration, indicating that up-regulated alpha5 integrin is responsible for an immobile phenotype. In addition, in the SCID mouse model, SF invasion into cartilage was attenuated by glucocorticoid treatment in vivo. CONCLUSION: Glucocorticoids increase integrin expression and the adhesion of cells to fibronectin, inhibit ERK signaling, and down-regulate the invasiveness of SFs in vivo. This study demonstrates that an important antiinflammatory aspect of glucocorticoids is regulating the expression and function of alpha5 integrin.