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To evaluate the use of starting doses of rofecoxib and nabumetone in patients with osteoarthritis (OA) of the knee.A 6-week, randomized, parallel-group, double-blind, placebo-controlled study.One hundred thirteen outpatient sites in the United States.A total of 1,042 male and female patients aged 40 and older with OA of the knee (>6 months).Rofecoxib 12.5 mg once a day (n=424), nabumetone 1,000 mg once a day (n=410), or placebo (n=208) for 6 weeks.The primary efficacy endpoint was patient global assessment of response to therapy (PGART) over 6 weeks, which was also specifically evaluated over the first 6 days. The main safety measure was adverse events during the 6 weeks of treatment.The percentage of patients with a good or excellent response to therapy as assessed using PGART at Week 6 was significantly higher with rofecoxib (55.4%) than nabumetone (47.5%; P=.018) or placebo (26.7%; P 5 days, P

Oral glucocorticoids (GCs) are widely used and despite their adverse effects on bone mineral density, the risk of sustaining osteoporotic fractures is not well addressed. The objective of this retrospective, cohort study was to assess fracture risk in patients exposed to oral GCs. Patients from an administrative claims database who were prescribed oral GCs and were enrolled 1 year before and 1 year after the initial oral GC claim were matched with a comparison population on age, sex, and date of first claim. Measurements of exposure included amount, duration, and pattern of oral GC use. The osteoporosis-related risk of fracture was based on the ratio of hazard functions estimated using a Cox proportional hazards model. The adjusted relative risk (RR) estimates (and 95% CI) for fractures were hip 1.87 (95% CI, 1.2 to 2.9), vertebral 2.92 (95% CI, 2.0 to 4.3), wrist/forearm 1.03 (95% CI, 0.8 to 1.4), nonvertebral 1.68 (95% CI, 1.5 to 1.9), any fracture 1.75 (95% CI, 1.6 to 1.9). A dose dependence of fracture risk was observed for hip, vertebral, nonvertebral, and any fractures. Long duration and continuous pattern of GC use demonstrated a significant 5-fold increased risk of hip and 5.9-fold increased risk of vertebral fracture. The combined effect of higher dose, longer duration, and continuous pattern further increased RR estimates to 7-fold for hip and 17-fold for vertebral fractures. This study confirms previous observations that suggest oral GCs have a rapid deleterious effect on trabecular-rich bone. The emerging relationship between amount, duration, and pattern of oral GC exposure and fracture risk should be considered in clinical practice and managed care settings to avoid the debilitating effects of fractures in patients.

THERE IS NO INNOCENT EYE. THE PHOTOS OF A STARVING SOMALIAN CHILD AND THE REPORT OF A MASSACRE IN ALGERIA COME FROM AND BRING WITH THEM POINTS OF VIEW

HOW MUCH DO WE BELIEVE THE LIES WE TELL TO OURSELVES AND OTHERS?

Objective To determine the potential for additive or synergistic effects of combination therapy with the selective anti–tumor necrosis factor α agent etanercept and the anti–interleukin-1 agent anakinra. Methods Two hundred forty-four patients in whom rheumatoid arthritis (RA) was active despite methotrexate therapy were treated with subcutaneous etanercept only (25 mg twice weekly), full-dosage etanercept (25 mg twice weekly) plus anakinra (100 mg/day), or half-dosage etanercept (25 mg once weekly) plus anakinra (100 mg/day) for 6 months in a double-blind study at 41 centers in the US. Patients had never previously received anticytokine therapy. Patient response was measured with the American College of Rheumatology (ACR) core set criteria, a health-related quality-of-life questionnaire, and the Disease Activity Score. Safety was assessed by the number of adverse events and clinical laboratory values. Plasma concentrations of both agents and antibody formation against both agents were also assessed. Results Combination therapy with etanercept plus anakinra provided no treatment benefit over etanercept alone, regardless of the regimen, but was associated with an increased safety risk. Thirty-one percent of the patients treated with full-dosage etanercept plus anakinra achieved an ACR 50% response, compared with 41% of the patients treated with etanercept only. This result was not statistically significant (P = 0.914). The incidence of serious infections (0% for etanercept alone, 3.7–7.4% for combination therapy), injection-site reactions, and neutropenia was increased with combination therapy. Combination therapy had no effect on the pharmacokinetics or immunogenicity of either agent. Conclusion Combination therapy with etanercept and anakinra provides no added benefit and an increased risk compared with etanercept alone and is not recommended for the treatment of patients with RA.

Objective To determine whether prasterone administration results in improvement or stabilization of systemic lupus erythematosus (SLE) disease activity and its symptoms. Methods Women with active SLE were treated with prasterone 200 mg/day plus standard SLE treatments or with placebo plus standard SLE treatments for up to 12 months in this randomized, double-blind investigation conducted at 27 centers. Standard SLE treatments included prednisone (≤10 mg/day), antimalarials, and immunosuppressive agents; dosages were required to be stable for ≥6 weeks prior to enrollment and remain unchanged during protocol treatment. Responders were patients who experienced no clinical deterioration and had improvement or stabilization over the duration of the study in 2 disease activity measures (the SLE Disease Activity Index [SLEDAI] and the Systemic Lupus Activity Measure) and 2 quality of life measures (patient's global assessment and the Krupp Fatigue Severity Scale). Results A total of 381 women with SLE were enrolled. Among patients with clinically active disease at baseline (SLEDAI score >2), 86 of 147 in the prasterone group (58.5%) demonstrated improvement or stabilization without clinical deterioration, as compared with 65 of 146 in the placebo group (44.5%) (P = 0.017). Acne and hirsutism were reported in 33% and 16%, respectively, of the prasterone group and in 14% and 2%, respectively, of the placebo group (P < 0.05 for both comparisons). However, most cases of acne and hirsutism were mild and did not require withdrawal from therapy. Myalgias and oral stomatitis were reported less frequently in the prasterone group (22% and 15%, respectively) than in the placebo group (36% and 23%, respectively) (P < 0.05 for both comparisons). Serum levels of high-density lipoprotein cholesterol, triglycerides, and C3 complement significantly decreased, while levels of testosterone and, to a lesser extent, estradiol increased in the prasterone group. Conclusion In adult women with active SLE, administration of prasterone at a dosage of 200 mg/day improved or stabilized signs and symptoms of disease and was generally well tolerated.

Purpose. The objective of this study was to evaluate synovial sarcomas for the expression of oncogenic proteins (Her2/neu, EGFR, Bcl-2, p53) and proliferation markers (Ki-67, Topoisomerase 2α), as possible markers of prognostic significance. Methods. From 17 patients with synovial sarcomas 19 tumors (15 primary, 2 recurrent, and 2 metastatic) were selected on the basis of characteristic histology, the expression of at least one epithelial marker, and/or the presence of t(X;18). Adequate follow-up was available in all cases. Results. The tumors were tested immunohistochemically and were found to express multiple oncogenic proteins. Four of 19 synovial sarcomas (21%) demonstrated nuclear over-expression of p53 protein; 18 of 19 tumors (94%) stained positive for Bcl-2; and 13 of 19 tumors (68%) were immunoreactive with EGFR. Of particular interest was the frequent expression of Her2/neu, an oncogenic protein more commonly observed in epithelial neoplasms. Ten of 19 tumors (52%, 7 monophasic and 3 biphasic) showed positive cytoplasmic and membranous staining with Her2/neu (HercepTest, DAKO). The staining intensity ranged from 1+ to 2+. Cellular expression of Her2/neu was independent of EGFR positivity and showed no association with proliferative activity of the tumors. FISH analysis of eight positive cases showed no evidence of Her2/neu gene amplification. Among the non-metastatic tumors, we found a significant correlation between Ki-67 and Topoisomerase 2α. Spearman's correlation co-efficient was 0.86 with P=0.001 (n=17). Conclusions. In this relatively small series of cases, we found no definite correlation between the over-expression of Her2/neu and clinical outcome. The over-expression of p53 was significantly associated with clinical outcome (Fisher's exact test, P=0.02).

Objective To evaluate the safety and efficacy of 2 dosages of cevimeline for the treatment of xerostomia and keratoconjunctivitis sicca in patients with Sjogren's syndrome. Methods A 12-week double-blind, randomized, placebo-controlled study was performed. Patients were randomly assigned to receive either placebo, 15 mg of cevimeline 3 times daily, or 30 mg of cevimeline 3 times daily. Patients were evaluated at baseline and throughout the study for their global assessment of dryness (mouth, eyes, overall) as well as their subjective assessment of the specific symptoms of dry mouth and dry eyes. Total saliva and tear flow also were measured. Results Patients taking 30 mg of cevimeline 3 times daily had statistically significant improvements in their subjective global assessment of dry eyes (P = 0.0453), dry mouth (P = 0.0004), and increased salivary flow (P = 0.007). Patients receiving the 30-mg dosage also showed greater objective improvement (increased salivary and lacrimal flow rates, as measured by Schirmer's test) than did patients receiving placebo. Frequently reported adverse events included headache, increased sweating, abdominal pain, and nausea. Conclusion Treatment with cevimeline at a dosage of 30 mg 3 times daily resulted in substantive improvement by increasing the rate of saliva and tear flow in patients with Sjogren's syndrome, as well as improving subjective symptoms of dry mouth, dry eyes, and overall dryness. The 15-mg dosage relieved some symptoms, and both dosages were well tolerated.

The epidermal growth factor receptor (EGFR) is a multisited and multifunctional transmembrane glycoprotein with intrinsic tyrosine kinase activity. Upon ligand binding, the monomeric receptor undergoes dimerization resulting in kinase activation. The consequences of kinase stimulation are the phosphorylation of its own tyrosine residues (autophosphorylation) followed by association with and activation of signal transducers. Deregulation of signaling resulting from aberrant expression of the EGFR has been implicated in a number of neoplasms including breast, brain, and skin tumors. A mutant epidermal growth factor (EGF) receptor missing 267 amino acids from the exoplasmic domain is common in human glioblastomas. The truncated receptor (EGFRvIII/DeltaEGFR) lacks EGF binding activity; however, the kinase is constitutively active, and cells expressing the receptor are tumorigenic. Our studies revealed that the high kinase activity of the DeltaEGFR is due to self-dimerization, and contrary to earlier reports, the kinase activity per molecule of the dimeric DeltaEGFR is comparable to that of the EGF-stimulated wild-type receptor. Furthermore, the phosphorylation patterns of both receptors are similar as determined by interaction with a conformation-specific antibody and by phosphopeptide analysis. This eliminates the possibility that the defective down-regulation of the DeltaEGFR is due to its altered phosphorylation pattern as has been suggested previously. Interestingly, the receptor-receptor self-association is highly dependent on a conformation induced by N-linked glycosylation. We have identified four potential sites that might participate in self-dimerization; these sites are located in a domain that plays an important role in EGFR functioning.

Objective Three 6-12-month, double-blind, randomized, controlled trials have shown leflunomide (LEF; 20 mg/day, loading dose 100 mg x 3 days) to be effective and safe for the treatment of rheumatoid arthritis (RA). This analysis of the North American trial assessed whether the clinical benefit evident at month 12 was sustained over 24 months of treatment with LEF as compared with the efficacy and safety of methotrexate (MTX), an equivalent disease-modifying antirheumatic drug, at 24 months. Methods The year-2 cohort, comprising patients continuing into the second year of treatment with > or = 1 dose of study medication and > or = 1 followup visit after week 52, consisted of 235 patients (LEF n = 98; placebo n = 36; MTX n = 101). The mean (+/- SD) maintenance dose of LEF was 19.6 +/- 1.99 mg/day in year 2 and that of MTX was 12.6 +/- 4.69 mg/week. Statistical analyses used an intent-to-treat (ITT) approach. Statistical comparisons of the active treatments only were prospectively defined in the protocol. Results In total, 85% and 79% of LEF and MTX patients, respectively, who entered year 2 completed 24 months of treatment. From month 12 to month 24, the American College of Rheumatology improvement response rates of > or = 20% (LEF 79% versus MTX 67%; P = 0.049), > or = 50% (LEF 56% versus MTX 43%; P = 0.053), and > or = 70% (LEF 26% versus MTX 20%; P = 0.361) were sustained in both of the active treatment groups. The mean change in total Sharp radiologic damage scores at year 2 compared with year 1 and baseline (LEF 1.6 versus MTX 1.2) showed statistically equivalent sustained retardation of radiographic progression in the active treatment groups. Maximal improvements evident at 6 months in the Health Assessment Questionnaire (HAQ) disability index (HAQ DI) and the physical component score of the Medical Outcomes Survey 36-item short form were sustained over 12 months and 24 months; improvement in the HAQ DI with LEF4(-0.60) was statistically significantly superior to that with MTX (-0.37) at 24 months (P = 0.005). Over 24 months in the ITT cohort, serious treatment-related adverse events were reported in 1.6% of the LEF-treated patients and 3.7% of the MTX-treated patients. Frequently reported adverse events included upper respiratory tract infections, diarrhea, nausea and vomiting, rash, reversible alopecia, and transient liver enzyme elevations. Conclusion The safety and efficacy of LEF and MTX were maintained over the second year of this 2-year trial. Both active treatments retarded radiographic progression over 24 months. LEF was statistically significantly superior to MTX in improving physical function as measured by the HAQ DI over 24 months of treatment. Results indicate that LEF is a safe and effective initial treatment for active RA, with clinical benefit sustained over 2 years of treatment without evidence of new or increased toxicity.

Over the last several years the two pre-eminent professional societies representing rheumatology, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), have been discussing increasing their collaboration in areas of interest to rheumatologists worldwide. These discussions resulted in a letter of agreement in 2008 on the framework whereby the two organisations would work together to develop disease classification criteria as well as recommendations for conducting of clinical trials. To enhance communication between the two organisations, ACR representatives now sit on the EULAR Standing Committee for Clinical Affairs and the EULAR Standing Committee of Epidemiology, and EULAR representatives now sit on the ACR Criteria Subcommittee and Quality of Care Committee. The first result of this effort was the joint publication, in Annals of the Rheumatic Diseases and Arthritis Care & Research , of the recommendations on reporting disease activity in clinical trials of patients with rheumatoid arthritis (RA).1 2 This document was important in that it delineated the minimal standards necessary for clinical trials evaluating new therapeutics in RA. Several collaborative projects are under way on RA, and also on gout, scleroderma, myositis and vasculitis. The positive aspects of developing a consensus between the dominant voices in world of rheumatology are self-evident. The recent initiative to revise the ACR classification criteria for RA3 is the most significant cooperation so far. For the past 2 years rheumatologists on both sides of the Atlantic have been working on this project, and the fruits of their work are …

Objective To compare the safety, tolerability and efficacy of the new oral microemulsion formulation of cyclosporin A (CyA; Sandimmun Neoral) and the original CyA formulation (Sandimmun), in patients with severe active rheumatoid arthritis (RA), over a 12-month period. Methods In this double-blind, multicentre study, patients were randomized to treatment with Neoral or Sandimmun, starting with 2.5 mg/kg/day, with dose adjustments after 4 weeks. Primary efficacy criteria included patients' assessment of disease activity. Pharmacokinetic and safety assessments were performed at regular intervals. Results Compared with Sandimmun, Neoral showed a consistent trend towards greater clinical efficacy from week 12 onwards, including a significant difference in patients' assessment of disease activity at the study end-points. A significantly lower increase in dose from baseline was observed with Neoral at week 24. Pharmacokinetic assessments at week 24 showed increased absorption and decreased variability with Neoral. No differences in safety were found between treatment groups. Conclusion These observations indicate that Neoral is as safe and at least as effective as Sandimmun and have important implications for patient management given the increasing role for CyA in the treatment of severe, active RA.

Objective Risedronate, a new pyridinyl bisphosphonate, is a potent antiresorptive bone agent. This study examines the safety and efficacy of daily, oral risedronate therapy for the prevention of corticosteroid-induced bone loss. Methods This multicenter, randomized, double-blind, placebo-controlled, parallel-group study was conducted in 224 men and women who were initiating long-term corticosteroid treatment. Patients received either risedronate (2.5 mg or 5 mg) or placebo daily for 12 months. Each patient also received 500 mg of elemental calcium daily. The primary outcome measure was the percentage of change in lumbar spine bone mineral density (BMD). Secondary measures included proximal femur BMD and incidence of vertebral fractures. Results After 12 months, the lumbar spine BMD (mean ± SEM) did not change significantly compared with baseline in the 5-mg (0.6 ± 0.5%) or the 2.5-mg (−0.1 ± 0.7%) risedronate groups, while it decreased in the placebo group (−2.8 ± 0.5%; P < 0.05). The mean differences in BMD between the 5-mg risedronate and the placebo groups were 3.8 ± 0.8% at the lumbar spine (P < 0.001), 4.1 ± 1.0% at the femoral neck (P < 0.001), and 4.6 ± 0.8% at the femoral trochanter (P < 0.001). A trend toward a decrease in the incidence of vertebral fracture was observed in the 5-mg risedronate group compared with the placebo group (5.7% versus 17.3%; P = 0.072). Risedronate was well tolerated, and the incidence of upper gastrointestinal adverse events was comparable among the 3 groups. Conclusion Risedronate therapy prevents bone loss in patients initiating long-term corticosteroid treatment.

The interaction of 800-MeV ${\mathrm{H}}^{\mathrm{\ensuremath{-}}}$ ions with a thin foil produces protons, the ground state and excited states of neutral ${\mathrm{H}}^{0}$ atoms, and unstripped ${\mathrm{H}}^{\mathrm{\ensuremath{-}}}$ ions. We investigated the distributions of individual ${\mathrm{H}}^{0}$ Stark states within the $n=3$ and 4 levels produced by C and ${\mathrm{Al}}_{2}{\mathrm{O}}_{3}$ foil stripping of ${\mathrm{H}}^{\mathrm{\ensuremath{-}}}$ ions. Foils of various thicknesses were placed upstream of a magnet with a linearly increasing transverse field along the beam direction producing a motional electric field strong enough to ionize ${\mathrm{H}}^{0}$ states with $ng~3.$ We consider three questions: (i) What are the populations of individual ${\mathrm{H}}^{0}$ Stark states produced in the interaction of 800-MeV ${\mathrm{H}}^{\mathrm{\ensuremath{-}}}$ ions with thin C and ${\mathrm{Al}}_{2}{\mathrm{O}}_{3}$ foils, (ii) how do the relative population distributions change with foil thickness, and (iii) how is the population distribution produced in an ${\mathrm{Al}}_{2}{\mathrm{O}}_{3}$ foil modified when the foil is placed in a magnetic field? A simple qualitative model is presented to explain the major trends.

We have previously shown that apoptosis induced in thymocytes by dexamethasone or teniposide (VM-26) could be inhibited by 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7) and sangivamycin, both relatively specific inhibitors for protein kinase C, but not by N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA1004), a more specific inhibitor for cAMP-dependent protein kinases. Apoptosis in this model system was not blocked by EGTA and no increase in cytosolic Ca2+ was observed during apoptosis induced by either dexamethasone or VM-26, suggesting that this kinase was Ca2+-independent. In the present study, we demonstrate that addition of 10 microM sangivamycin to thymocyte cultures up to 2 h after addition of either inducer resulted in virtually complete inhibition of apoptosis. Addition of 10 microM sangivamycin at 3 or 4 h after addition of inducer resulted in partial inhibition of apoptosis. Computerized image analysis of two-dimensional PAGE analyses of whole-cell lysates demonstrated that treatment of mouse thymocytes with VM-26 resulted in a limited number of de novo phosphorylation events within 1 h of treatment. The most prominent phosphorylation events associated with VM-26-induced apoptosis were that two intracellular protein species (Protein 1: m.w. = 22.9 kDa, pI, 5.11; and Protein 2: m.w. = 22.9 kDa, pI, 4.98). Similar phosphorylation events were seen in cells treated with dexamethasone. Finally, Western blot analysis suggests that de novo protein phosphorylation induced by VM-26 is on serine/threonine residues. These results provide further evidence that the mechanism of VM-26-induced apoptosis of murine thymocytes involves the action of one or more serine/threonine kinases.

Background Flares or onset of inflammatory bowel disease in association with immunosuppression has been reported in the literature. Methods We studied 4 cases of patients with rheumatic disease who developed or had a flare of ulcerative colitis either after initiation of or while taking a tumor necrosis factor- α inhibitor. Results We identified 4 patients, three male and one female. Two of the male patients had a seronegative spondyloarthropathy and one had rheumatoid arthritis. The female patient had amyopathic dermatomyositis. Two of the 4 patients had ulcerative colitis prior to tumor necrosis factor- α treatment. Both of these patients had quiescent ulcerative colitis that flared after they began taking etanercept. Two patients developed de novo ulcerative colitis while taking a tumor necrosis factor- α inhibitor. Conclusions The data presented in these 4 cases supports a temporal relationship between initiating a tumor necrosis factor- α inhibitor and onset or flare of ulcerative colitis. These observations raise the possibility that tumor necrosis factor- α inhibitor therapy, which has been used as treatment for inflammatory bowel disease, may rarely be a factor in the development of disease.

L'A. souligne que les conferences jouent un role fondamental dans la vie des communautes de chercheurs notamment en sciences sociales. Il presente un certain nombre de donnees concernant l'organisation de conferences dans le domaine de la criminologie. Il examine de quelle maniere les themes des conferences sont selectionnes. Il montre comment le type et le lieu de la conference sont choisis. Il analyse la signification de la presence d'un universitaire dans le cadre d'une conference. Il met en lumiere les modes de presentation des exposes. Il souligne qu'une conference vise a etablir une interaction entre les differents chercheurs. Il montre de quelle maniere les conferenciers et leurs familles sont accueillis lors de ce type de reunion

Biological organisms and their component organs, tissues and cells have unique electrical impedance properties. Impedance properties often change with changes in structure, composition, and metabolism, and can be indicative of the onset and progression of disease states. Over the past 100 years, instruments and analytical methods have been developed to measure the impedance properties of biological specimens and to utilize these measurements in both clinical and basic science settings. This chapter will review the applications of impedance measurements in the biomedical sciences, from whole body analysis to impedance measurements of single cells and cell monolayers, and how cellular impedance measuring instruments can now be used in high throughput screening applications.

Israeli Jews are too locked in to their own domestic conflicts to care about what happens to the Palestinians. Peace is precarious and ‘reconciliation’ a long way off

Measurements of ${\mathrm{H}}^{\ensuremath{-}}$ stripping and ${\mathrm{H}}^{0}$ excited-state production for a wide range of foil thicknesses and experimental conditions are reported. An 800-MeV ${\mathrm{H}}^{\ensuremath{-}}$ beam was passed through carbon or aluminum oxide foils of thicknesses ranging from 10 to 550 \ensuremath{\mu}g/${\mathrm{cm}}^{2}$ and the excited states produced were analyzed by field stripping in a special magnet downstream of the foil. The foil thicknesses were independently determined. The ${\mathrm{H}}^{0}$ atoms emerging in excited states with $ng2$ can be stripped to protons in fields of up to 1.3 T. The yield of excited states as a function of foil thickness and the cross sections for the various interactions are presented. The cross-section ratio of double to single ionization of ${\mathrm{H}}^{\ensuremath{-}}$ in carbon is found to be (1.8\ifmmode\pm\else\textpm\fi{}0.9)%.

absolute duty to convey the truth, to bear witness. There are many types of human rights reports. The major international nongovernmental organizations (such as Human Rights Watch and Amnesty International) produce regular and detailed book-length reports. These are the equivalent of social science research projects, giving a comprehensive account of a particular country's current human rights record. Then there are the simplest reports-legal or journalistic, rather than social scientificgiving information only on a single case or problem. Other variants include entries in annual world-wide atlases of human rights violations, press releases, regular documentation by regional and national organizations, results of fact-finding missions, publications of academic human rights centers, and official documents from intergovernmental organizations within the UN orbit.

‘A camera in the right hands at the right time in the right place can be more powerful than tanks and guns’ Peter Gabriel announcing the ‘Witness Program’

In this report, we describe the isolation from human urine of a predominant 160-kDa epidermal growth factor (EGF)-immunoreactive glycoprotein that exhibits affinity for heparin. The purification procedure involved concentration and dialysis of 20-30-liter batches of fresh urine on a high capacity ultrafiltration apparatus followed by chromatography on DEAE-Sephacel, heparin-agarose, and Sephacryl S-300. A nearly homogeneous preparation of 160-kDa protein was obtained with a yield of approximately 1 mg of 160-kDa protein from 25 liters of urine. The amino-terminal sequence of the purified 160-kDa protein, H2N-SAPQHXSXPEGTXA-, matched residues 21-34 of the predicted sequence of human prepro-EGF and established that the 160 kDa protein (pro-EGF) is a product of the prepro-EGF gene. Characterization of the carboxyl terminus of the purified protein by digestion with carboxypeptidase B and by immunoblotting with antisera against synthetic carboxyl-terminal and juxtatransmembrane peptides of prepro-EGF indicated that the carboxyl terminus has been truncated at an arginine residue that corresponds, most likely, to the carboxyl-terminal arginine of the EGF moiety. The intact 160-kDa pro-EGF is biologically active as evidenced by its specific binding to the EGF receptor and activation of the EGF receptor tyrosine kinase in A-431 cell membranes. Purified pro-EGF competitively inhibited the binding of 125I-EGF to human fibroblasts, and it stimulated the proliferation of these cells in culture. When immobilized onto culture dishes, the heparin-binding pro-EGF appeared to function both as an adhesion molecule and as a growth factor for serum-free mouse embryo cells.

The activation of Janus protein-tyrosine kinases (Jaks) and the subsequent phosphorylation and activation of latent signal transducers and activators of transcription (Stats) are common elements in signal transduction through the cytokine receptor superfamily. To assess the role and specificity of Jaks in Stat activation, we have utilized baculovirus expression systems to produce Stat1 and the Jaks. Co-expression of Stat1 with Tyk2, Jak1, or Jak2 resulted in the specific tyrosine phosphorylation of Stat1 at Tyr701, the residue phosphorylated in mammalian cells stimulated with interferon gamma. Alternatively, Stat1, purified to apparent homogeneity from insect cell extracts, was phosphorylated at Tyr701 in Jak immune complex kinase reactions. Phosphorylation of purified Stat1 was necessary and sufficient for the acquisition of DNA binding activity. The specificity in both systems was indicated by the inability of a Jak2 catalytically inactive mutant (Jak2-Glu882) or the Tec protein-tyrosine kinase to phosphorylate Stat1. However, immune complex-purified epidermal growth factor receptor was capable of phosphorylating purified Stat1 at Tyr701 and activating its DNA binding activity in in vitro reactions.

Background: No published data exist on the incidence of liver fibrosis in patients with dermatomyositis treated with methotrexate. Objective: Our purpose was to examine the efficacy, steroid-sparing potential, and side effects of methotrexate in patients with dermatomyositis and to report liver biopsy results in four patients. Methods: A retrospective review of all cases of dermatomyositis treated with methotrexate in a dermatology and rheumatology referral practice was conducted. Results: Of the 10 cases reviewed, seven were of dermatomyositis whereas three were of amyopathic dermatomyositis (ADM). Nine patients received oral methotrexate. One patient received intravenous methotrexate. Improvement of cutaneous disease occurred in seven (100%) of the patients with dermatomyositis and in two (66%) of those with ADM; myositis improved in four (57%) of the patients with dermatomyositis. The initial prednisone dose was halved after an average of 18 weeks of methotrexate therapy in the patients with dermatomyositis and 13 weeks in the patients with ADM. Methotrexate-related side effects occurred in six (86%) of the patients with dermatomyositis and in one (33%) of the patients with ADM. Of the four patients who had liver biopsies, two (50%) showed mild hepatic fibrosis, resulting in discontinuation of the drug. Both patients in whom fibrosis developed had preexisting steroid-induced diabetes mellitus. Conclusion: Although methotrexate is an effective treatment for dermatomyositis, side effects are common. Patients with diabetes mellitus should be closely monitored for toxic effects on the liver.

Background Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). In a Phase 3, 12-month (Mo) study (ORAL Standard) including RA patients (pts) on stable background methotrexate (MTX), tofacitinib and adalimumab (ADA) demonstrated significant improvements in efficacy outcomes compared with placebo (PBO).1 Objectives To evaluate the efficacy of tofacitinib and ADA based upon American College of Rheumatology (ACR) component scores in a post-hoc analysis of ORAL Standard. Methods ORAL Standard (NCT00853385) was a randomised, multicentre, Phase 3 study investigating the efficacy of oral tofacitinib 5 and 10 mg twice daily (BID) or ADA 40 mg administered subcutaneously (SC) every two weeks vs PBO in MTX inadequate responders. All pts received background MTX. Effects of tofacitinib 5 mg BID vs ADA 40 mg SC were evaluated in exploratory, post-hoc analyses at Mo 3, 6, 9 and 12 of the proportion of pts achieving ACR 20/50/70 response as well as the change from baseline in each of the following ACR components: Health Assessment Questionnaire-Disability Index (HAQ-DI), tender and swollen joint counts (TJC and SJC), Patient9s Global Assessment (PtGA), erythrocyte sedimentation rate (ESR), Physician9s Global Assessment (PGA), C-reactive protein (CRP) and Pain. For ACR response rates, pts who withdrew before Mo 12 were considered non-responders from that visit onward. The normal approximation approach to binomial proportions was used to analyse the ACR response. A mixed-effect model was applied to analyse the change from baseline data. Treatment differences for tofacitinib 5 mg BID vs ADA 40 mg SC were reported along with 95% confidence intervals. All analyses were descriptive and were not adjusted for multiplicity. Results Overall, ACR20/50/70 response rates were numerically higher for tofacitinib 5 mg BID vs ADA over the 12 mo. At Mo 6 ACR20/50/70 rates for tofacitinib were 60.6%, 38.9%, 19.7% vs 57.9%, 28.9%, 9.1%, for ADA. At Mo 12 ACR20/50/70 rates for tofacitinib were 59.6%, 43.5%, 24.9%, vs 61.4%, 38.6%, 16.8% for ADA. Comparable changes from baseline were reported for tofacitinib vs ADA in HAQ-DI, ESR, TJC, SJC, CRP, PtGA, PGA and Pain over time, with numerically higher improvements observed for tofacitinib in the majority of ACR components (Table). Previously published safety data from this study showed that infections and infestations were the most frequent AEs reported over 12 mo in both tofacitinib and ADA treatment groups.1 Serious infection events were more frequent in tofacitinib 5 and 10 mg BID treatment groups (3.4% and 4.0%, respectively) compared with ADA (1.5%), over 12 Mo.1 Conclusions These post-hoc analyses show that efficacy was generally similar in comparing tofacitinib with ADA, with numerical differences in favour of tofacitinib in some efficacy parameters. The ORAL Standard study was not designed or powered for statistical comparisons between ADA and tofacitinib. Prospective studies to investigate the effect of tofacitinib compared with ADA are under way. References van Vollenhoven RF et al. N Engl J Med 2012; 367: 508–519. Acknowledgement This study was sponsored by Pfizer Inc. Editorial support was provided by R Bright, PhD, of Complete Medical Communications and funded by Pfizer Inc. Disclosure of Interest R. van Vollenhoven Grant/research support from: Pfizer Inc, Consultant for: Pfizer Inc, S. Cohen Grant/research support from: Pfizer Inc, Consultant for: Pfizer Inc, A. Mendelsohn Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, E. Bananis Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, H. Fan Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Takiya Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Fleischmann Grant/research support from: Pfizer, AbbVie, Consultant for: Pfizer, AbbVie

Purpose SBI-087 is a Small Modular Immunopharmaceutical Protein™(SMIP™) drug that binds to CD20 and has been reported to deplete B cells in murine/primate studies. The safety, tolerability and pharmacokinetic/pharmacodynamic properties of SBI-087 were evaluated in patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). Methods Single-dose SBI-087 was evaluated in 2 Phase I, open-label, escalating-dose studies in patients with RA or SLE. The studies included 6 IV/4 SC escalating doses (RA) and 1 IV/4 SC escalating doses (SLE). Escalation was determined by tolerability/rate of B-cell depletion. Serum was collected for analyses of pharmacokinetic and pharmacodynamic (CD19 + B cells) properties and immunogenicity. Patients were followed until B-cell counts were normalized or stabilized. Safety, tolerability was evaluated from adverse events, physical examinations, vital sign measurements, ECG, and clinical laboratory results. Findings Sixty patients with RA (IV, 28; SC, 32) and 30 patients with SLE (6 per cohort) were enrolled. Mild to moderate infusion reactions occurred in several patients at the top doses in the RA study despite a pretreatment regimen of IV doses. Unanticipated reactions after SC administration of SBI-087 included fever, chills, and malaise, seen on the day of dosing in the lowest-dose cohorts in both studies. These events were abrogated in subsequent cohorts by a pre/postdose treatment regimen consisting of oral corticosteroids, acetaminophen, and an antihistamine. SBI-087 clearance (IV) ranged from 22 to 229 mL/h; volume of distribution at steady state ranged from 5 to 12 L. Apparent clearance (SC) ranged from 44.7 to 105 mL/h; volume of distribution ranged from 14.3 to 32.1 L. Overall, PK properties were similar at equivalent doses between IV/SC administrations in patients with RA/SLE. Mean t ½ (IV) ranged from 2.1 to 10.7 days (less at lower doses). SBI-087 concentration and B-cell depletion were generally dose proportional across IV and SC cohorts. However, the extent of B-cell depletion was less, and rate of repletion was faster, in patients with SLE versus RA. In both studies, B-cell repletion to baseline did not occur in the majority of patients by the end of the observation period. Overall, the prevalence and type of adverse events were similar to those seen with other anti-CD20–depleting agents. Implications In patients with mild RA/SLE, SBI-087 was well tolerated when administered intravenously or subcutaneously with pre- and posttreatment regimens. B-cell depletion is long lasting, and the duration and extent of depletion may be greater in RA compared with SLE. SBI-087 exhibited slow elimination and low distribution in both populations. Clinicaltrials.gov identifiers: NCT00641225 (RA) and NCT00714116 (SLE).

Background Dose escalation is a common strategy for patients (pts) having an inadequate response to a medication. Objectives To examine low disease activity (LDA) among pts receiving infliximab (IFX) who did and did not escalate therapy above 3mg/kg in CORRONA, a US national registry of rheumatoid arthritis (RA) pts. Methods We identified all RA pts who initiated IFX on or after 6/2009 at a dose ≤3mg/kg and with moderate or high disease activity (CDAI>10). Eligible pts required at least 6 mos of follow-up after initiation or after dose escalation. Dose escalation was defined as an increase of >1mg/kg or reduction in infusion intervals by ≥1 wk. We divided pts into 3 groups: pts achieving LDA (CDAI ≤10) without dose escalation; pts not achieving LDA and not dose escalating; pts dose escalating. The last group was further divided into pts achieving LDA after dose escalation and pts not achieving LDA after dose escalation. We compared the populations at time of initiation by demographics, BMI in categories of normal (BMI Results There were 286 pts who met inclusion criteria. 124 (43.4%) reached LDA without escalation; 50 (17.5%) either switched without escalation or had not reached LDA by at least 9 mos; 112 (39.2%) escalated. Of the escalators, 64 (57.1%) reached LDA and 48 (42.9%) switched or did not reach LDA by at least 9 mos. Pts who reached LDA without escalation were more likely to be biologic naive (67.7%) than those who escalated but did not reach LDA (45.8%, p=0.008). Pts reaching LDA without escalation had lower disease activity measures at initiation (tender joints, physician global assessment, pt global assessment, pt pain) than pts not reaching LDA with or without escalation (p Conclusions Pts more likely to reach LDA without dose escalation are biologic naive and have lower disease activity measures at initiation. Both high BMI (obese) and diabetes are associated with requiring dose escalation to achieve LDA. In this analysis, ≤25% of patients received dose escalation beyond 8mg/kg/8wks, which may have clinical relevance. Acknowledgement Study sponsored by Corrona, LLC. Corrona RA registry has been supported thru contracted subscriptions in last 2 yrs by AbbVie, Amgen, BMS, Crescendo, Genentech, Horizon Pharma USA, Janssen, Eli Lilly, Novartis, Pfizer, & UCB. Disclosure of Interest S. Cohen Grant/research support from: Amgen, Biogen-IDEC, BMS, Centocor, Genentech, Johnson & Johnson, Pfizer, Merck, and Roche, G. Reed Shareholder of: Corrona, LLC, Employee of: Corrona, LLC, R. Magner Employee of: Corrona, LLC, S. Kafka Employee of: Janssen Scientific Affairs, LLC, L. Ellis Employee of: Janssen Scientific Affairs, LLC, R. DeHoratius Employee of: Janssen Scientific Affairs, LLC, J. Greenberg Shareholder of: Corrona, LLC, Consultant for: Janssen Scientific Affairs, LLC, AstraZeneca, Celgene, Genentech, Novartis, Pfizer, Employee of: Corrona, LLC

Background European and US guidelines recommend MTX as part of initial treatment for patients with RA.1,2 Biologic agents are recommended for patients with poor prognostic indicators and those who fail to achieve treatment goals after 3–6 months of conventional therapy.1,2 Currently, it is not clear how closely these recommendations are being followed in the US. Objectives To assess patterns of treatment for patients who initiated DMARD treatment in the US in either 2009 or 2012 and were followed for at least 2 years. Methods The analysis used Symphony Health Solutions9 anonymized patient-level claims data which captures ∼274 million US patients. Analysis included RA patients identified by ICD-9 codes 714.0 and 714.30 who initiated treatment with either oral MTX or a biologic therapy in 2009 or in 2012 and were followed for 2 years. Information obtained included: demographic characteristics, initial treatments, switches from oral to subcutaneous (SC) MTX and/or biologics (with or without concomitant MTX), timing of treatment changes, and oral MTX or SC MTX dosing at the times of switches/additions or end of follow-up. Results The study included 48,910 patients who initiated treatment in 2009 and 107,636 who started treatment in 2012 (Table). For the RA patients who started treatment in 2009, 27.1% initiated therapy with a biologic and 72.9% started on oral MTX. The respective values for patients initiating therapy in 2012 were 35.6% and 64.4%. Over the first 2 years of follow-up, 35.2% of patients who started MTX in 2009 and 21.6% of those started on MTX in 2012 switched to a biologic or had one added to MTX. A small percentage of patients in each cohort switched from oral to SC MTX. The median duration of oral MTX treatment prior to switching to or adding a biologic was 60 days for patients who initiated treatment in 2009 and 177 days for those who initiated MTX in 2012. Conclusions In the US, a large percentage of RA patients receive a biologic without a prior trial of MTX and this approach to treatment increased from 2009 to 2012. While there is a trend toward underuse of MTX as initial treatment from 2009 to 2012, a higher percentage of patients who started MTX in 2012 remained on this treatment for at least 2 years vs those started in 2009. This suggests many clinicians may not be following best practice with regard to the use of SC MTX. References Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73:492–509. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2016;68:1–26. Acknowledgement Study sponsored by Medac Pharma, Inc. Disclosure of Interest J. O9Dell: None declared, S. Cohen Grant/research support from: Abbvie, Amgen, Astellas, Medac, Pfizer, UCB, C. Thorne Grant/research support from: Abbive, Amgen, Celgene, CaREBiodam, Lilly, Novartis, Pfizer, Sanofi, UCB, Consultant for: Abbvie, Centocor, Genzyme, Hospira, Medexus, Pfizer, Paid instructor for: Abbvie, Centocor, Genzyme, Hospira, Medexus/Medac, Pfizer, T. Mikuls Grant/research support from: Roche/Genentech, Consultant for: Pfizer

Objective.This 5-year observational posthoc analysis of the REFLEX study and its open-label extension assessed clinical efficacy, radiographic response, and safety of rituximab (RTX) in patients with rheumatoid arthritis (RA) who had an inadequate response to tumor necrosis factor (TNF) inhibitors.Methods.Patients in REFLEX were originally randomized to placebo (PBO) + methotrexate (MTX; PBO-randomized) or RTX + MTX (RTX-randomized). PBO-randomized patients were rescued with RTX as appropriate. Patients responding to initial RTX treatment could receive further RTX courses. For clinical efficacy and safety analyses, PBO-randomized patients were re-baselined prior to first RTX treatment and the data were pooled with RTX-randomized patient data. Efficacy outcomes 24 weeks after each course were calculated relative to first RTX pretreatment baseline. Radiographic outcomes were assessed relative to randomization baseline for both PBO-randomized and RTX-randomized groups.Results.A total of 480 patients received ≥ 1 RTX course. At 24 weeks, American College of Rheumatology 20/50/70 responses were 62.0%, 30.8%, and 13.0%, respectively at course 1 (n = 400) and 70.3%, 41.8%, and 22.0% at course 5 (n = 91). European League Against Rheumatism good/moderate responses were 77.2% and 84.4% at courses 1 (n = 390) and 5 (n = 90). Rates of adverse events (AE), serious AE, and infections generally remained stable. Rate of progressive joint damage (PJD; change in mean Total Sharp Score) decreased over time in both PBO-randomized (n = 79) and RTX-randomized (n = 105) groups. Mean change from baseline in PJD over 5 years was greater in PBO-randomized versus RTX-randomized patients (5.51 vs 3.21).Conclusion.RTX re-treatment over 5 years is associated with maintained or improved efficacy, continued inhibition of PJD, and a safety profile consistent with that previously reported. A delay in initiating RTX treatment may result in increased PJD.

Background Studies examining the relationship between serological status (rheumatoid factor and/or anticitrullinated antibody) and rituximab treatment outcome in rheumatoid arthritis (RA) have been hampered by limited numbers of seronegative patients. Objective To carry out a meta-analysis of trials from the rituximab RA clinical programme to investigate this relationship further. Methods This was a meta-analysis of four placebo-controlled, phase II or III clinical trials. The efficacy end point in all analyses was change from baseline in Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) at 24 weeks. Assay of serotype and missing data imputation methods were consistent across all studies. Results The population analysed comprised 2177 patients (rituximab, n=1416; placebo, n=761). Demographics and baseline disease characteristics were well balanced. When a fixed-effects meta-analysis approach was used, the overall-effect model indicated evidence of additional treatment benefit with rituximab in seropositive patients: reduction in DAS28-ESR at week 24 was on average 0.35 units (95% CI 0.12 to 0.84; n=1394) greater than in seronegative patients; this effect was not seen in placebo patients. Heterogeneity indices indicated significant uncertainty in the overall-effect model (Q=8.8, I=0.77; p=0.03 (χ 2 test)). Baseline Health Assessment Questionnaire score, pain visual analogue scale, swollen joint counts of 28 joints and race were significant contributors to this heterogeneity, with additional analysis indicating that these effects may predominate in early RA (methotrexate-naive) populations. A dominant effect was seen in patients for whom one or more tumour necrosis factor inhibitors had failed. Conclusion Although the difference was modest, the overall-effect model indicates that seropositive patients respond better to rituximab than seronegative patients.